HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (54) Citing Articles via Google Scholar Google Scholar Articles by Hebert, D. N. Articles by Molinari, M. Search for Related Content PubMed PubMed Citation Articles by Hebert, D. N. Articles by Molinari, M.

In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases

Institute for Research in Biomedicine, Bellinzona, Switzerland; and Department of Biochemistry and Molecular Biology, Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, Massachusetts

ABSTRACT

I. INTRODUCTION

A. From Genes to Proteins

B. Protein Synthesis

C. Protein Folding

II. PROTEIN TRANSLOCATION, FOLDING, AND QUALITY CONTROL IN THE ENDOPLASMIC RETICULUM

A. Protein Targeting to the ER

B. Chaperone-Assisted Protein Folding in the ER

1. The classical chaperones

2. The lectin chaperones

3. The link between BiP and the lectin chaperone system

4. Disulfide bond formation

5. Peptidyl-prolyl cis-trans isomerization

6. Substrate-specific chaperones

7. Cotranslational folding

C. ER-Associated Protein Degradation

1. The efficiency of protein folding

2. The importance of understanding ER-associated protein degradation

3. Misfolded proteins produced in the ER are degraded in the cytosol

4. Protein quality control in the ER: the unfolded versus misfolded conundrum

5. A timer ticking in the ER lumen

6. Protein demannosylation in the ER lumen

7. The EDEM triad as ERAD regulator

8. Cytosolic lectins prepare ERAD candidates for destruction

9. Viral gene products to assess mechanisms of ERAD

10. Alternative degradation pathways

11. ERAD in yeast compared with higher eukaryotes

III. CONFORMATIONAL AND ENDOPLASMIC RETICULUM STORAGE DISEASES

A. Human Diseases Caused by Defective Protein Folding or Trafficking: Selected Examples

B. Pharmacological and Chemical Chaperones to Rescue Structurally Defective, Functional Proteins

IV. CONCLUDING REMARKS

GRANTS

ACKNOWLEDGMENTS

REFERENCES

	ABSTRACT

Top Next References

	I. INTRODUCTION

Top Previous Next References

 
A. From Genes to Proteins

The flow of genetic information from DNA to RNA to proteins constitutes the basis for cellular life. The replication of the genome is extremely accurate. Correction mechanisms such as editing and repair ensure error rates below 1 x 10^–8 in bacteria and 1 x 10^–10 in eukaryotes (288). To a certain extent, mutations in the genomic DNA sequence are tolerated and give essential contribution to the evolution process, provided they do not result in replacement of residues essential for the polypeptide's biologic activity, or in mutations, deletions, or premature termination of the polypeptide chain that prevent protein maturation. The information transfer from DNA to mRNA (transcription), from mRNA to linear strings of amino acid chains (translation), and the conversion of the latter into a correctly shaped and biologically active protein (folding) are error-prone. Sporadic errors in gene transcription (estimated at 1 x 10^–4 in bacteria) or translation (see Table 1) as well as a certain level of folding inefficiency rarely have dramatic consequences for cell survival because both messengers and proteins have relatively short half-lives relative to the organisms life span and may rapidly be replaced by new gene products. Moreover, quality control mechanisms are in place to select faulty products to be selectively removed (83, 167).

Protein synthesis is operated by ribosomes, macromolecular machines made by ribosomal rRNAs, and several small ribonucleoproteins that act as scaffold. The large (60S) and the small (40S) ribosomal subunits assemble at the AUG start codon at the 5' -end and disassemble at the UAG/UGA/UAA stop codon at the 3' -end of mRNAs. Transfer tRNAs presenting matching triplet anticodons serve as amino acid donors to elongate nascent polypeptides at a rate of 4–5 amino acids/s in mammalian cells (300).

Ribosomes are free in the cytosol, in mitochondria, and in chloroplasts or associated at the cytosolic face of the ER membrane. Cytosolic ribosomes synthesize cytosolic, nuclear, and peroxisomal proteins as well as most proteins of mitochondria and chloroplasts. Membrane-bound ribosomes synthesize polypeptides destined to the secretory and endocytic compartments (ER, Golgi, endosomes, and lysosomes), to the plasma membrane, and for secretion to the extracellular space. Translation has an infidelity rate estimated at 1 amino acid in 10³ –10⁴ (57, 288). Errors are caused by misacylation leading to tRNAs loaded with the inappropriate amino acid (221), by selection of an incorrect tRNA during the elongation process (176, 231), by incorrect selection of the start codon, by frame shifts, or by incorrect terminations. During the synthesis of the polypeptide chain (cotranslational phase) and after the release of the newly synthesized polypeptide from the ribosome (posttranslational phase), the folding of the polypeptide chain converts the string of amino acids into a mature, active protein that is eventually displayed at the appropriate intra- or extracellular location.

C. Protein Folding

High fidelity of gene expression is a basic requirement for life of single and multicellular organisms. Rapid and efficient conversion of the information contained in the linear sequence of amino acids in the unique native shape of every one of the individual polypeptides produced by cells is of crucial importance and must fulfill thermodynamic and kinetic requirements. Studies performed in test tubes in the early 1960s (6, 7, 407) revealed that only the information contained in the amino acid sequence is required for proper folding of polypeptides and that the unique native state of a protein in its physiologic milieu is the one in which the Gibbs free energy of the whole system is lowest (5). The free-surface energy of the "protein-cellular milieu" system is largely increased by exposure of hydrophobic groups. Hence, burial of nonpolar residues or patches in the core of the molecule starts the protein folding process, thus rapidly minimizing free-surface energies. Hydrophilic interactions such as salt bridges and disulfide bonds limit the number of folding states explored by the folding polypeptides, thus allowing termination of the folding process in a biologically acceptable time span.

Whereas few model denatured proteins can refold spontaneously in the absence of cellular factors in vitro, protein folding in cells involves other proteins that act as molecular chaperones and as folding enzymes that accelerate rate-limiting reactions in the folding process. They are hosted in all cell compartments and organelles in which protein synthesis or posttranslational protein import occurs. They belong to families that have been conserved during evolution. Small heat shock proteins (Hsp), and proteins of the Hsp40, Hsp60, Hsp70, Hsp90, and Hsp100 families act as molecular chaperones and selectively bind nonnative determinants exposed by folding, incompletely assembled polypeptides, or by polypeptides that enter off-pathways eventually leading to irreversible misfolding and destruction (85, 136).

Molecular chaperones are not by definition part of the final polypeptide functional structure and do not convey structural information. They do not normally accelerate the kinetics of the folding process. Folding enzymes or foldases are responsible for accelerating rate-limiting steps for the folding reaction. Protein disulfide isomerases (PDI) catalyze formation of covalent bonds between cysteine residues of a polypeptide. Peptidyl-prolyl cis-trans isomerases (PPI) catalyze isomerization of peptidyl-prolyl bonds. These two chemical reactions would be too slow if not assisted enzymatically.

The observation that proteins can be ubiquitylated cotranslationally (333) and might actually be degraded before chain termination if they carry specific degradation signals at their NH₂ terminus (381) show that folding and degradation of a given polypeptide chain may be in kinetics competition (268a). Certainly, folding and degradation are strongly interconnected as it has been established that a functional degradation machinery is required for maintenance of protein folding capacity (86, 114, 268). Despite availability of numerous ER-resident folding assistants, the protein folding process may fail and is substantially affected by errors in the polypeptide sequence. Products derived from faulty genes may be incapable of acquiring functional shapes. These defective products can either be rapidly degraded causing loss-of-function phenotypes or accumulate in or outside cells leading to gain-of-toxic-function phenotypes. Both of these outcomes can cause a number of human diseases, many of which are familial. In this review, we have collected the information available on mechanisms regulating the efficient transfer of information from DNA to functional proteins. In particular, we focus our attention on the fate of proteins that enter the eukaryotic secretory pathway by cotranslational translocation into the ER. We describe how these proteins fold and are processed with the assistance of resident ER proteins. We explain what is currently understood about how the ER quality control machinery monitors the fidelity of the maturation process and targets aberrant proteins for destruction. Finally, we discuss the pathological consequences of aberrant folding and/or defective degradation of mutated gene products causing several human diseases. Detailed knowledge of the events regulating protein folding, quality control, and degradation may offer therapeutic opportunities to treat these conformational or ER storage diseases.

	II. PROTEIN TRANSLOCATION, FOLDING, AND QUALITY CONTROL IN THE ENDOPLASMIC RETICULUM

Top Previous Next References

 
A. Protein Targeting to the ER

Mammalian ribosomes are only located in the cytosol and in mitochondria. For proteins to be expressed in the ER lumen, two issues must therefore be resolved: 1) how to bring translating ribosomes in close proximity to the ER membrane and 2) how to get the nascent polypeptide chains across the ER membrane. Several groups contributed in the elucidation of these mechanisms. In the early 1950s, Palade (299) showed that in secretory cells a large population of ribosomes is associated with endomembranes. Ten years later, compelling data demonstrated that mRNA for cytosolic proteins is translated on free ribosomes while mRNA for secretory proteins is translated on membrane-bound ribosomes (106, 151, 318) and that membrane-bound ribosomes vectorially discharge nascent polypeptide chains across the ER membrane (319, 320, 331). Finally, it has been established that the in vitro translation product of immunoglobulin light chain was larger than the mature protein expressed in vivo (123, 238, 259, 335, 338, 364, 374) due to the presence of a string of 20 hydrophobic residues preceding the NH₂ terminus of the mature secretory protein (336). This led to the hypothesis (26, 259) and later to the demonstration (25) that short signal sequences subsequently removed from mature proteins serve as address tags for protein synthesis at the ER membrane.

A complex of 7S RNA and six polypeptides named signal recognition particle (SRP) binds the signal sequence emerging from the ribosome, thus slowing down chain elongation (397, 398) until the ribosome engages a proteinaceous channel located at the ER membrane and formed by two Sec61 heterotrimeric complexes (see sect. IIB7) (120, 261). Only then, protein synthesis is resumed, the short hydrophobic tag is usually removed, and nascent chains are cotranslationally injected into the ER lumen (116, 257, 399). Beyond the function as address tags, signal sequences may have specific posttargeting functions such as regulation of gene expression (245) or of virus assembly (426). Recent data show that the efficiency of polypeptide targeting by signal sequences is variable and may affect the biosynthetic load of the ER during conditions of ER stress (187, 365).

The ER lumen has unique conditions [e.g., is more oxidizing compared with the cytosol (166)], and several proteins expressed in this compartment are subjected to peculiar co- and posttranslational modifications such as the formation of intra- and interchain disulfide bonds between cysteines and addition of preassembled oligosaccarides and lipid anchors. The discrepancy between in vitro and in vivo folding rates led to the discovery of an enzyme system which catalyzes the rate-limiting step of protein folding in the ER by participating in the formation of native disulfides between the cysteine residues of a maturing protein (118, 390). Nearly half a century of further study clearly showed that complex mechanisms and machineries have evolved to facilitate polypeptide folding, to control the quality of the products, to distinguish native proteins to be transported at their site of activity from aberrant, folding-defective side products of protein biogenesis to be rapidly removed from cells. A basic set of molecular chaperones and folding enzymes has been conserved from eubacteria to higher eukaryotes (137). In addition, in eukaryotes, more sophisticated systems are also in operation.

B. Chaperone-Assisted Protein Folding in the ER

Protein folding in the ER commences cotranslational/translocationally and continues posttranslationally until the native protein structure is reached. The high concentration of calcium ions and oxidizing conditions of the ER create an environment that is topologically equivalent to the extracellular milieu. As an intracellular maturation compartment, the ER prepares secretory proteins to remain stable under challenging extracellular conditions. The ER houses factors that assist proteins in their folding and supports the attachment or formation of protective and stabilizing covalent modifications. Ultimately, properly folded and assembled proteins are packaged into cytosolic coat protein II (COPII)-derived vesicles and transported out of the ER to the Golgi.

1. The classical chaperones

Cellular compartments in which synthesis or translocation of proteins occurs (cytosol, mitochondria/chloroplasts, and ER) contain a high concentration of molecular chaperones that prevent aggregation of unfolded chains, facilitate protein maturation, and retain folding proteins in appropriate micro- or macroenvironments enriched with folding enzymes. Classical chaperones are grouped in several subfamilies, namely, Hsps of 40, 60, 70, 90, and 100 kDa in size (Table 2). The ER lumen does not contain members of the Hsp60 (chaperonins) family; rather, it possesses a member of the Hsp70 family [glucose-regulated protein (GRP)78/BiP (128, 146)]; BiP cofactors classed in the Hsp40 [ERdj1–5 (344)] and GrpE-like families [BAP/Sil1 (56) and GRP170 (358, 405)]; a member of the Hsp90 family [GRP94 (220)]; and a member of the Hsp100 family [TorsinA (32)]. Cytosolic members of the Hsp families are transcriptionally induced upon temperature stress; ER-resident members are not, but their synthesis is strongly enhanced under conditions of ER overload, glucose deprivation, or upon unbalanced calcium or redox conditions homeostasis (220, 347).

BiP shields immature proteins from aggregation by promiscuously binding to extended hydrophobic domains with relatively low affinity (1–100 mM). Affinity panning of a bacteriophage expressed peptide library demonstrated that BiP has a preference for alternating aromatic and hydrophobic amino acids (27). These alternating residues can localize to a single surface to support BiP binding. A BiP binding score or algorithm for predicting BiP interacting regions was developed from these results, which can be used to identify potential BiP binding regions. On average, proteins are expected to contain a hydrophobic Hsp70 interacting region once every 36 residues, underscoring the broad range of substrates these proteins are expected to bind during their maturation (330). Consistently, a number of maturing viral and host cell proteins have been found to transiently associate with BiP (128, 133, 312). The binding of BiP to misfolded mutant proteins can be prolonged and, as shown by analysis of transthyretin (TTR) variants, there might be a direct correlation between thermodynamic and kinetic instability of the TTR variants, and BiP capture (354). Moreover, association of BiP with covalent and noncovalent aggregates of misfolded proteins signaled a role of BiP in maintenance of solubility of aberrant proteins to facilitate their eventual disposal (40, 184, 264, 284, 354).

BiP contains two main functional domains: a COOH-terminal peptide binding domain that is controlled by its NH₂-terminal ATPase domain. ADP binding to BiP creates the high-affinity conformation, whereas ATP binding supports peptide release or its low-affinity conformation. J-proteins are thought to deliver substrates to Hsp70 and initiate the hydrolysis of ATP by Hsp70, thereby preparing the high-affinity form of the chaperone. Recent studies have identified several ER J-proteins called ERdj1/Mtj1 (34, 50), ERdj2/hSec63 (349, 382), ERdj3/HEDJ/ERj3/ABBP-2 (24, 217, 432), ERdj4/Mdj1 (313, 344, 345), and ERdj5/JPDI that has both a J domain and oxidoreductase activity (61, 158). All these proteins bind BiP in vitro and stimulate its ATPase activity. In addition, nucleotide exchange factors assist in the swapping of ADP bound to Hsp70s for ATP. These factors help create the low-affinity binding conformation leading to the release of peptide by Hsp70. The bacterial exchange factor GrpE is the most thoroughly studied. The recently discovered nucleotide exchange factor BAP/Sil1 (56) and GRP170 (358, 405) appear to serve this role in the ER lumen.

BiP levels are tightly controlled and are elevated upon physiological (e.g., cell differentiation increasing the ER load with cargo proteins) or pathological (accumulation of misfolded proteins) stress responses. During embryogenesis, BiP expression remains below detection limit to the morula stage, but becomes abundant at the blastocyst stage in E3.5 embryos (196). It is therefore not surprising that the BiP^–/– mice cannot survive beyond this stage, and the cells when cultured in vitro cannot proliferate and rapidly degenerate (235). A partial reduction in the level of BiP is tolerated as BiP^+/– embryos and adult mice are normal. The essential role of BiP in cell, tissue, and organism homeostasis is underscored by the identification of BiP as the cellular target of one of the most potent bacterial toxins ever characterized, the subtilase cytotoxin (SubAB). SubAB is produced by a highly virulent Shiga toxigenic Escherichia coli strain responsible for the 1998 outbreak of hemolytic uremic syndrome in Southern Australia. SubAB inactivates BiP through a single-site cleavage that disconnects the substrate binding from the ATPase domain of the molecular chaperone (269, 302). The disruption of BiP activity results in rapid cell death.

GRP94 is the most abundant glycoprotein in the ER. Whereas BiP is evolutionarily conserved from yeast to human, GRP94 is only found in vertebrates (220). GRP94 appears to associate with more advanced folding intermediates than BiP, since it binds some substrates after they have been released from BiP (253). It helps with the maturation of immunoglobulin heavy chains, integrin, and toll-like receptors (253, 317). GRP94 is comprised of three distinct domains, which include 1) an NH₂-terminal regulatory domain, 2) a central substrate-binding domain, and 3) a COOH-terminal dimerization domain. Nucleotide binding to the NH₂-terminal domain appears to control substrate binding; however, the precise mechanism of regulation is largely unknown (77, 170, 352). GRP94 does not appear to act as an ATPase or have cofactors like its cytosolic paralog, Hsp90. Geldanamycin, which competes for the ATP binding site on the NH₂ terminus of GRP94, inhibits substrate binding and has been used to determine the necessity of GRP94 binding for protein maturation (360). In addition to its role in protein maturation, GRP94 is also known for its ability to induce T-cell immunity (226). Here, it uses its ability to bind small peptides as an antigen delivery system, thereby initiating MHC class I-restricted T-cell response against a variety of pathogenic or cellular antigens. Overall, cells have evolved a diverse set of roles for the fundamental substrate binding properties of the hsp70 and hsp90 chaperones of the ER that extend far beyond their central function in assisting in protein maturation (220).

2. The lectin chaperones

The majority of the proteins that traverse the secretory pathway receive multiple N-linked glycans. These hydrophilic modifications can change the general properties of proteins. They also provide binding sites for carbohydrate-binding chaperones. In contrast to BiP that binds directly to the hydrophobic backbone of the polypeptide, the lectin chaperones bind the glycans or the bulky hydrophilic extensions. However, both chaperone systems appear to serve similar roles in increasing the overall fidelity of the maturation process.

Preassembled glycans composed of three glucose, nine mannose, and two N-acetyl glucosamine residues (Glc₃Man₉GlcNAc₂, Fig. 1) are transferred by the oligosaccharyl transferase (OST) from a lipid pyrophosphate donor in the ER membrane, dolichol-PP, to nascent polypeptide chains (301). Oligosaccharides covalently modify the side chain of asparagines in Asn-X-Ser/Thr consensus sites (Fig. 1).

View larger version (15K): [in this window] [in a new window]   FIG. 1. Structure of N-linked oligosaccharides. The high mannose precursor covalently attached to Asn-X-Ser/Thr sequences of nascent polypeptide chains normally contains 9 mannose residues. Cell lines with defective synthesis of mannosylphosphoryldolichol are characterized by addition of incomplete oligosaccharides with only 5 mannose residues. A, B, C, and D are 1,2-bonded mannose residues that are removed by members of the glycosyl hydrolase family 47 (refer to Fig. 5). Glucose 1 is removed by the glucosidase I; glucose residues 2 and 3 are both removed by the glucosidase II.

Both calnexin and calreticulin were initially named for their ability to bind calcium (97, 395). Calnexin is a type I membrane protein that contains a single luminal carbohydrate binding domain. The calnexin crystal structure demonstrates that the carbohydrate-binding domain is formed by a -sandwich structure commonly found in leguminous lectins (339). A long hairpin extends away from the carbohydrate-binding domain forming a second domain termed the P-domain. The P-domain named for its richness in Pro residues creates an arm that recruits an accessory oxidoreductase involved in disulfide bond formation and isomerization called ERp57 (103, 210). Calreticulin is a soluble paralog of calnexin (258). While its crystal structure has yet to be solved, its strong homology to calnexin implies that it will have a similar organization, containing a single carbohydrate-binding domain with a slightly shorter P-domain.

Since calnexin and calreticulin bind monoglucosylated glycans with micromolar affinities (188), their chaperone binding cycles are controlled by the glucosidases and transferase that dictate the carbohydrate composition on maturing glycoproteins in the ER (132, 140, 144, 279, 295, 296, 356). Glucosidases I and II sequentially remove glucose 1 and glucose 2 (Fig. 1), respectively. This generates the monoglucosylated glycans that support the initial binding to the lectin chaperones (Fig. 2, step 1). Glucosidase II is a soluble, heterodimeric glycanase composed of a regulatory () and a catalytic () subunit (379). The regulatory -subunit is dispensable for the enzyme activity in vitro (378). However, it has been shown that yeast lacking the glucosidase II -subunit fails to remove glucose 3 but can still cleave glucose 2 (412). The -subunit is a sequence homolog of the mannose-6-phosphate receptor. The association of the -subunit with mannoses in the 6'-tetramannosyl branch of a core N-glycan has been recently proposed to cause a change in the conformation and result in the proper positioning of the catalytic -subunit for removal of glucose 2 from an additional N-glycan unit (74). Consistent with this transactivation model, the presence of more than one N-glycan is required for the formation of a complex between calnexin and nascent chains in canine microsomes and semipermeabilized cells (325, 400). Transactivation may not be strictly required for glucosidase II action as the enzyme can efficiently process, at least in vitro, methotrexate conjugates displaying a single oligosaccharide (375).

View larger version (83K): [in this window] [in a new window]   FIG. 2. The fate of newly synthesized glycoproteins in the ER lumen. Nascent chains enter the ER lumen through the Sec61 complex. They are core glycosylated by the oligosaccharyltransferase (OST). The two terminal glucose residues are rapidly trimmed by sequential action of the glucosidase I and II (step 1). Mono-glucosylated N-glycans mediate initial association of folding polypeptides with the ER lectin chaperones calnexin and/or calreticulin and exposure to the glycoprotein-dedicated oxidoreductase ERp57. It is likely that most glycopolypeptides are released from calnexin/calreticulin/ERp57 in a native, transport competent state (step 2). They are rapidly deglucosylated and partially demannosylated (step 3) and eventually sequestered in transport vesicles that leave the ER (step 4). For a fraction of newly synthesized glycoproteins, folding is not completed in a single round of association with calnexin/calreticulin (step 2a). The folding intermediate released from the lectin chaperones is deglucosylated (step 3a), but its forward transport is inhibited by GT1. GT1 adds back a glucose residue (step 4a) only to glycoproteins with nearly native conformation. These rebind to calnexin/calreticulin and are subjected to additional folding attempts likely to consist in disulfide reshuffling. Glycopolypeptides released from calnexin and displaying major folding defects are ignored by GT1 (step 3b). Rather, they attract BiP. They are extensively demannosylated and dislocated across the ER membrane for proteasome-mediated degradation (step 4b).

Calnexin and calreticulin binding exposes maturing substrates to ERp57 (a glycoprotein-dedicated oxidoreductase, Fig. 2) and generally slows the folding reaction helping to increase its overall efficiency (145). Pharmacological inhibition of the lectin chaperone binding with glucosidase inhibitors can lead to faster folding, premature oligomerization, and reduced folding efficiencies. For folding-defective polypeptides, the bypass of the calnexin system normally results in accelerated onset of the degradation program (141; see below). Posttranslational addition of glucosidase inhibitors preserves the N-glycans in a monoglucosylated state, which inhibits release from calnexin and calreticulin, and may arrest the global folding and oxidation of glycoproteins (139). Therefore, as with the traditional chaperones discussed above, protein folding appears to take place in the unbound form, with chaperone binding helping to control the rate of the folding process and minimizing disruptive interactions that would lead to the formation of terminal aggregates. Glycoproteins may fold properly after a single round of binding to the lectin chaperones (Fig. 2, green arrows). However, cycling by the lectin chaperones as controlled by glucosidase II and GT (yellow arrows) can lead to proper maturation and transport (green arrows) or ERAD (red arrows).

Having two lectin chaperones with different topologies helps to broaden the scope of substrates that can be assisted. Calnexin binds to glycans found in membrane proximal domains while the soluble calreticulin associates with glycans that emerge deeper into the ER lumen (142). These two lectin chaperones can act to protect a wide range of substrates or work together to assist glycoproteins that possess both membrane proximal and distal glycans. Expression of calreticulin possessing an added membrane anchor in HepG2 cells demonstrated that substrate selection by membrane-associated calreticulin was similar to calnexin, indicating the importance of membrane topology in chaperone recognition (393).

While carbohydrate binding by calnexin and calreticulin is the central determinant for substrate selection, they also appear to be able to bind directly to the protein backbone in some cases (13, 45, 394; reviewed in Ref. 414). In addition, purified calreticulin and the soluble ectodomain of calnexin can bind and inhibit the in vitro aggregation of nonglycosylated proteins (63, 414). Future studies will be needed to identify where the polypeptide-binding domain is localized on these chaperones and how this binding is regulated.

Deletion of individual members of the calnexin/calreticulin chaperone system is well-tolerated in cultured cells (351 and references therein), but it results in embryonic lethality in mice for GT1 (265), ERp57 (108) and calreticulin (254) deletions. Calnexin deletion causes severe growth and motor disorders, and premature death (73). The lethal outcome of an inherited glucosidase I deficiency (67) confirms that the calnexin/calreticulin chaperone system plays an essential role during protein biogenesis possibly restricted to specific organs or developmental phases. In cultured cells, folding of most polypeptides must progress quite normally because individual chaperone deletions do not result in evident signs of ER stress (108, 263, 265, 351). However, there are at least two relevant exceptions that include influenza virus hemagglutinin (HA) that suffers substantial folding defects when expressed in cells lacking calnexin (263, 307), ERp57 (351), or GT1 (351a) and major histocompatibility complex (MHC) class I molecules that are loaded with suboptimal peptides and show premature release at the surface of calreticulin (107) or ERp57-deficient cells (108).

3. The link between BiP and the lectin chaperone system

Association of newly synthesized glycoproteins with the BiP system often precedes association with calnexin and calreticulin (133, 266, 309, 373, 389, 400). Exceptions are glycoproteins displaying N-glycans in the very NH₂-terminal portion of the molecule (266). As N-glycosylation and association with calnexin/calreticulin occur as fast as when 12 residues emerge in the ER lumen (3, 282), this excludes BiP assistance to the nascent chain (266 and references therein). BiP can also intervene after substrate release from the calnexin system to bind extensively misfolded polypeptides (18, 40, 68, 76, 98, 113, 162, 184, 203, 239, 243, 263–265, 354, 361, 363).

4. Disulfide bond formation

The formation of disulfide bonds is a critical step in the maturation of the majority of the proteins that traffic through the ER. The conditions of the ER favor the protein-assisted formation of disulfide bonds. Oxidoreductases from the PDI family (Table 3) catalyze these reactions by acting as electron acceptors in the oxidation reaction or electron donors for the converse reduction reaction. These enzymes can also isomerize disulfide bonds, helping a protein to obtain native disulfides by rearranging nonnative linkages (Fig. 3A). PDI family members are defined by containing CXXC motifs in thioredoxin domains. The number and location of these motifs vary depending on the particular enzyme (Table 3) (84).

View larger version (71K): [in this window] [in a new window]   FIG. 3. A: oxidation, reduction, and isomerization of disulfide bonds. B: isomerization of peptidyl-prolyl bonds.

The cysteines in the catalytically active domains of PDIs can be present in both the oxidized and reduced state. For the catalysis of disulfide bond formation in folding polypeptides, the CXXC motif contains a disulfide bond, acts as an electron acceptor, and leaves the reaction in the reduced state (Fig. 3A). In contrast for reduction of substrate disulfides, the CXXC motif of PDIs intervenes in the reaction in the reduced state (Fig. 3A). Finally, isomerization or disulfide rearrangement both starts and ends with the CXXC in the reduced state (Fig. 3A). A mixed disulfide with a substrate cysteine covalently bonded to a PDI reactive cysteine is a short living intermediate of all redox reactions described above. The oxidation state of the Cys residues found in the catalytic domain determines its function in the maturation process, and their redox state is controlled by its environment and additional proteins, which help to shuttle electrons into and out of the ER such as ERO1p (for review, see Ref. 380). In short, the membrane-associated flavoprotein ERO1 transfers oxidizing equivalents to PDI so that it can act as an oxidizing agent in the oxidation of nascent chains.

Although PDI family proteins are defined by their catalytic CXXC motifs that accelerate the formation and rearrangement of disulfide bonds, an essential function is also their chaperone activity. PDI can inhibit the aggregation of misfolded proteins that do not contain any disulfide bond (42). This activity does not require the active site Cys residues (316). This implies that PDI is not only a foldase that accelerates the folding reaction, but it can also act as a molecular chaperone to increase the fidelity of the folding reaction by inhibiting nonproductive aggregate formation. While the hydrophobic surface formed by the two central noncatalytic domains may play a role in the chaperone activity, how this binding is controlled is currently unknown.

The mammalian PDI family includes well over a dozen different proteins. Some of these proteins contain two TLD (PDI, ERp57, PDIp, PDILT, and P5); however, others have one (ERp18, ERp44, and TMX1–4), three (ERp72, ERP46, and PDIr), or even four of these motifs (ERdj5) (84) (Table 3). The canonical active site motif is the CXHC tetrapeptide characteristic of thiol-disulfide oxidants. It is found once in TMX and in ERdj5; twice in PDI, PDIp, ERp57, and P5; and three times in ERp72 (Table 3). A CXPC motif characteristic for thiol-disulfide reductants is displayed three times in ERdJ5. The other PDI family members display a variety of motifs lacking one or both terminal cysteines (Table 3 and Ref. 84 for a review). While it is expected that some of these proteins will serve redundant functions, future studies will be needed to understand the full scope of their roles. Initial studies indicated that a portion of these proteins interact with a particular subset of substrates while others serve specific roles in protein oxidation, reduction, or isomerization.

ERp57 (also called ER-60 and GRP58) possesses a similar domain organization to PDI but interacts specifically with glycoproteins due to its association with the P-domain of calnexin and calreticulin (237, 293, 294). A conserved positively charged region in the b' domain of ERp57 is responsible for lectin chaperone binding as found by mutagenesis, NMR spectroscopy, and isothermal titration calorimetry (103, 210, 218, 311). This region electrostatically interacts with a negatively charged region at the tip of the P-domains of calnexin and calreticulin (210). The lectin chaperones bind the nascent nonnative glycoprotein and position ERp57 to act upon the immature or misfolded glycoproteins possessing monoglucosylated side chains (267, 292, 294). ERp57 exhibits oxidoreductase activity towards a variety of glycosylated proteins (29, 102, 154, 182, 351, 357, 433).

The ERp57 knockout in mice represents the first successful deletion of an oxidoreductase from metazoan cells (108, 351). Influenza HA (351) and class I MHC molecules (108) emerge as the only model glycoproteins among those analyzed thus far to significantly suffer from the deletion of ERp57. Deletion of ERp57 does not affect cotranslational formation of disulfide bonds occurring during entry of HA in the ER lumen. It significantly impairs, however, the posttranslational phases of HA folding. These data were interpreted as an intervention of ERp57 in disulfide bond isomerization during substrate glycoprotein folding (351). Deletion of ERp57 also led to the identification of at least one PDI family member, ERp72, that can act as a surrogate chaperone in catalyzing intra- and intermolecular disulfide bond formation when ERp57 is absent (351). The residues in ERp57 that are involved in association with the P-domains of the lectin chaperones are conserved in ERp72 (77). However, in contrast to ERp57, substrate association with ERp72 remained unaffected by inhibition of substrate binding to calnexin (351). Deletion of ERp57 accelerates the release of MHC class I molecules from the peptide-loading complex, thus resulting in loading with suboptimal peptides and reduced expression and stability at the cell surface (108).

The large number of PDI family members includes enzymes with broad substrate specificity plus additional family members that appear to provide a wide range of specialized functions in the eukaryotic secretory pathway. PDI, ERp57, ERp72, and P5 have been found in functional complexes or transiently associated with folding substrates via mixed disulfides. PDIp is an abundant protein in the ER of pancreatic cells and therefore likely acts upon zymogens, the main pancreatic cargo (75). ERdj5 is an interesting fusion protein with a J-domain (suggesting cooperation with members of the Hsp70 chaperone family) associated with an oxidoreductase moiety (61, 158). ERp44 has been proposed to form a mixed disulfide with immature proteins and Ero1, thereby retaining them in the ER lumen (4) and to contribute in the regulation of ER calcium homeostasis by associating with the third luminal loop of the channel for calcium export from the ER lumen, the inositol 1,4,5-trisphosphate receptor 1 (152). ERp29 has evolved divergently from other PDI family members but retained the characteristic structural thioredoxin fold in one of its domains. Although the functional characterization of ERp29 is far from completion, all available data point to its important role in the early secretory pathway and allow tentative categorization as a secretion factor/escort protein of a broad profile (16). ERp29 has only a single Cys in its entire sequence, indicating that its catalytic site could only function as an isomerase. It initiates a conformation change in polyomavirus upon entry into the lumen of the ER (240). Therefore, ERp29 is likely used by viruses for their disassembly or uncoating in the lumen, which may involve the rearrangement of disulfide bonds found in their capsid proteins. Certainly, for the nearly 20 members of the PDI family, a number of unanswered questions remain about their structural features, their involvement in protein folding and/or degradation, their redundancy and interchangeability, their intracellular localization, and also about the molecular mechanisms regulating their activity.

5. Peptidyl-prolyl cis-trans isomerization

Most peptide bonds in native proteins are connected in trans conformation with the exception of Xaa-Pro bonds that can be found in both cis and trans conformations (Fig. 3B). Refolding experiments demonstrated that cis/trans isomerization of peptidyl-prolyl bonds (Fig. 3B) is a rate-limiting step of the polypeptide folding process (194). Prolyl isomerization is catalyzed by dedicated enzymes, the peptidyl-prolyl cis-trans isomerases (PPI) (95, 96). Mammalian cells contain three classes of PPI, namely, parvulins, cyclophilins (Cyps) and FK506-binding proteins (FKBPs) (121). The ER contains members of the two latter classes, namely, CypB and FKBP2, FKBP7, and FKBP10 (Table 4). CypB has been found in complexes containing several other ER chaperones (but not members of the calnexin chaperone system) (255, 435). It has also been reported to form functional complexes with Hsp47, a procollagen-specific chaperone in the ER (350). More recently, it has been reported that ER-resident members of the FKBP family can act as regulators of BiP activity (401, 436) and associate with BiP-bound substrates (65). Although they have been shown to significantly accelerate acquisition of native structure in refolding of denatured proteins in vitro, very little information is available on Cyps' and FKBPs' involvement in protein maturation in the living cell, and data supporting their activity remain, at the best, indirect.

While most proteins can fold properly with the assistance of the general chaperone systems, other proteins contain unique structures and/or are present at such a high concentration that specialized assistance is required. Substrate-specific chaperones in the ER include receptor-associated protein (RAP) and Hsp47. RAP facilitates proper folding and prevents aggregation and premature ligand binding by low-density lipoprotein (LDL) receptor (36, 224). It interacts with LDL receptors and helps escort the protein complexes to the Golgi. Hsp47 is a collagen-specific chaperone (278). Collagen is the most abundant mammalian protein, and it possesses an atypical triple-helical structure (185). While it interacts with many of the general chaperones (BiP, calnexin, and calreticulin) and folding factors (e.g., PDI), its proper maturation in the ER also requires Hsp47 (278). Mice with Hsp47 knocked out were deficient in collagen production and died 11.5 days postcoitus (277). The high expression level and unique structure of collagen appear to necessitate its requirement for a specifically tailored chaperone system. A comprehensive list of substrate-dependent chaperones can be found elsewhere (83).

7. Cotranslational folding

The average mammalian protein takes 2 min to be translated, and protein folding in vitro is measured on the millisecond time scale. Therefore, during a 2-min period of translation, extensive protein folding can occur. The Levinthal paradox demonstrates that this time frame is not sufficient to sample all possible conformations available for a given nascent chain to reach its native state (223). Instead, protein folding involves a more direct route to the native structure, assisted in the cell by the temporal and physical constraints placed on the maturing nascent chain, which help to minimize the structures available as folding intermediates. The source of some of these restrictions is that protein folding in the living cell begins while the protein is being translated by the ribosome. This process of cotranslational folding can assist the formation of the proper folded structure in several ways. First, it supports a vectorial folding process from the NH₂ to the COOH terminus, which restricts the number of conformations available to a newly synthesized chain. Second, the COOH terminus of the molecule is constrained by the ribosome further limiting the freedom of the nascent chain or the number of available folding intermediates. Third, the bulky ribosome separates the nascent chains of a polysome, preventing nonproductive collisions or aggregation. And fourth, it provides a mechanism for the cell to control and organize the environment of the vulnerable nascent chain. Together, these mechanisms act to optimize the cellular folding process.

For secretory cargo, folding starts both cotranslationally and cotranslocationally as the nascent chain emerges in the ER lumen through the Sec61 translocon. These proteins commonly possess NH₂-terminal signal sequences that target the protein to the ER. NH₂-terminal signal sequences of 20–30 amino acids are highly hydrophobic, supporting their integration into the ER membrane in a looplike configuration (143, 245). This places a further constraint on the maturing protein by tethering its NH₂ terminus to the membrane until the signal sequence is cleaved. The timing and efficiency of signal sequence cleavage by the signal sequence peptidase is substrate specific. Signal sequence cleavage of most proteins appears to occur cotranslationally. For the type I membrane proteins influenza HA and tyrosinase, cleavage takes place after 130 amino acids have been translated; however, the signal sequence for the HIV glycoprotein gp160 is removed posttranslationally (62, 225, 400). Delayed cleavage of gp160 appears to assist the proper folding of this complex viral protein.

Protease protection studies demonstrate that 40 amino acids can reside within the 100-Å-long tunnel of the ribosome (15, 248). Its narrow average diameter of 15 Å permits the folding of some -helices, as shown by fluorescent resonance energy transfer (FRET) measurements, but precludes the formation of more distal secondary structures (419). FRET studies have also found that a similar level of folding appears to be permitted within the narrow confines of the ER Sec61 translocon (419). In another study, the ribosomal and translocon-arrested Semliki Forest virus capsid protease domain was only able to fold when a linker of 64 amino acids or greater was placed at its COOH terminus, indicating that the protein could not fold to an active state in the translocon (209). Global protein folding is delayed until arrival in the lumen.

The inability for distal folding to take place in the translocon can be explained by recent structural studies, which have shed important light on the translocon architecture. The X-ray structure of the Sec61-related SecYE from the archaeon Methanococcus jannaschii in the absence of preprotein substrate indicates that the channel possesses an hour-glass shape with its narrowest diameter measuring 3 Å (385). Removal of the proposed plug domain at the center of the membrane would expand the channel to 17 Å. This value is in sharp contrast to 40–60 Å diameter measured for the functional mammalian Sec61 channel using fluorescence quenching studies (130). Recent cryoelectron microscopic studies of the E. coli Sec translocase suggest that it is composed of a dimer of heterotrimers, and a larger functional channel may be created by the joining of the two separate channels (80, 261).

Unless N-glycans are displayed at the polypeptide NH₂ terminus (266), BiP is the first luminal chaperone that interacts with nascent proteins upon emergence into the ER lumen (133, 253, 400). BiP is localized in part at the ER translocon entry site where it helps to maintain the permeability barrier also positioning it for early interactions with nascent chains (131). These associations help to drive the directionality of the translocating protein into the ER and protect the nascent chain during its most vulnerable state when it first emerges into the calcium-rich oxidizing environment.

N-linked glycans are generally added cotranslationally once the consensus glycosylation site is 75 residues away from the peptidyltransferase center (409). The membrane protein calnexin is the first carbohydrate-binding chaperone encountered by monoglucosylated glycoproteins, followed by the soluble calreticulin after the addition of further glycans or chain lengthening (62, 400). Calnexin appears to be recruited to the translocon site through a direct interaction between the ribosome and the cytoplasmic tail of calnexin, which may be regulated by phosphorylation of the calnexin tail (51). The association of lectin chaperones with nascent chains also supports cotranslational interactions with oxidoreductase ERp57 (49, 266, 267).

The translocon environment likely possesses some higher order organization that arranges ER proteins in an assembly line with a general order that allows proteins that act on earlier folding intermediates first (Fig. 4). Folding factors that act on near-native structures would be situated deeper into the lumen, away from the translocon for posttranslational associations. The extent of cotranslational folding and the timing and type of interactions are determined by the nascent chain sequence and structure. The polytopic protein cystic fibrosis transmembrane conductance regulator (CFTR) folds extensively cotranslationally while other proteins fold largely posttranslationally (178, 201).

View larger version (76K): [in this window] [in a new window]   FIG. 4. The translocon-associated environment encountered by the nascent chain. As proteins emerge into the ER cotranslational and cotranslocational through the Sec61 channel (purple membrane pore), they are subjected to a specialized maturation environment that facilitates their proper maturation. These factors include the signal peptide peptidase (SPC; 5 subunit complex), the oligosaccharyltransferase (OST; comprised of 8 or 9 subunits), glucosidases (GI and II), oxidoreductases (PDI and ERp57), and molecular chaperones [BiP, calnexin (Cnx), and calreticulin (Crt)].

C. ER-Associated Protein Degradation

1. The efficiency of protein folding

The efficiency of the folding process is strictly protein dependent and cannot be predicted based on the polypeptide sequence. Polypeptides for which acquisition of the correct tertiary and quaternary structures has failed are usually not transported through the secretory line (163, 327), even though exceptions do exist (see sect. IIC4; Ref. 127). Rather, they are dislocated into the cytosol, deglycosylated, ubiquitylated, and fragmented by the 26S proteasome (207). Further processing by the tripeptidylpeptidase II (322) and other peptidases (425) also occurs, until the fragments are reduced to single amino acids that can be recycled for protein biosynthesis. Controversial data have been published on the actual fraction of newly synthesized chains that never attain native structure and are rapidly degraded. These values range from upwards of 30% in one study (341) to substantially less in another (383).

Proteins can be ubiquitylated cotranslationally (333) and might actually be degraded before chain termination if they carry specific degradation signals at their NH₂ terminus (381). Protein degradation can also be anticipated and become cotranslational when cells are under ER stress and their survival requires a temporary decrease of the biosynthetic burden in the ER (297). Multicellular organisms could profit from a certain degree of folding inefficiency by producing wastes that may be used to monitor the protein set currently in production. To become immunologically relevant, the products of disposal of aberrant proteins must escape complete degradation to amino acids. Short peptides of at least eight amino acids are in fact reimported in the ER lumen through a heterodimeric transporter (TAP1/TAP2) member of the ATP-dependent transporter (ABC) superfamily (124), prepared for loading on class I MHC complexes and displayed at the cell surface for immunosurveillance (376). A high error rate during synthesis of viral proteins would result in surface presentation of viral epitopes, thus warning the immune system that the cell has been infected (337). However, heterologous proteins, such as viral gene products expressed in virus-infected cells, can sometimes show better capacity than the host cell proteins themselves to exploit the cellular folding environment to achieve native structure. Influenza HA folds with near 100% efficiency in infected cells (30). In contrast, biogenesis of the CFTR is a paradigm for cellular proteins with low folding-efficiency, which is further decreased upon gene mutations. It has been estimated that only 25% of the newly synthesized wild-type CFTR will eventually fulfill ER quality control requirements for transport to the cell surface, a percentage that drops to pathological levels in the case of mutant CFTR gene products (205, 402).

2. The importance of understanding ER-associated protein degradation

Understanding the mechanisms regulating degradation of folding-defective polypeptides expressed in the ER is one of the central issues in cell biology. Rapid disposal of folding-incompetent polypeptides produced in the ER lumen is instrumental to maintain ER homeostasis (256). The degradation machinery is easily saturated (377). Defective adaptation of the cellular degradation capacity to the ER load may result in accumulation of aberrant polypeptides that eventually impairs the ER capacity to assist maturation of newly synthesized secretory proteins (86).

The mechanisms evolved in metazoans to remove misfolded proteins from the ER lumen are exploited by a number of human pathogens. Bacterial toxins such as cholera and shiga toxin can travel through the secretory line in backflow and invade the host cell cytosol by crossing the ER membrane in a manner similar to ERAD substrates (233). Also, several viral gene products exploit the ERAD machinery to trigger degradation of host cell surface molecules such as viral receptors [e.g., the rapid degradation of the HIV1 receptor CD4 by the HIV1 gene product Vpu (104, 413)] or of molecules involved in immunosurveillance (e.g., the rapid disposal of class I MHC molecules by cytomegalovirus immunoevasins; see sect. IIC9).

The degradation machinery also regulates the intracellular level and activity of important cellular factors as exemplified by the case of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol biosynthesis (115) and the inositol 1,4,5-trisphosphate receptor (IP₃) (417). Elevation of the sterol levels increases by twofold the rate of degradation of HMG-CoA, thus controlling by negative feedback the cell production of cholesterol (54). IP₃R can be downregulated as part of an adaptive response by its polyubiquitination and subsequent degradation, which removes the calcium channel from the ER (417).

Finally, many loss-of-function human genetic diseases are caused by mutations that may not affect protein function, but slow significantly the kinetics of protein folding (refer to sect. III). In such cases, recognition by the ERAD machinery may precede completion of the folding process (268a). It is therefore clear that a detailed understanding of mechanisms regulating disposal of folding-defective and folding-incompetent proteins synthesized in the ER may eventually allow intervention in all the processes described above.

3. Misfolded proteins produced in the ER are degraded in the cytosol

Degradation of misfolded proteins synthesized in the ER requires energy and is unaffected by lysosomotropic agents, lysosomal enzyme inhibitors, and brefeldin A (a macrolide antibiotic that interferes with protein transport between ER and Golgi). These findings led initially to propose that nonnative polypeptides were retained and degraded in the ER lumen by a mechanism that involved ATP consumption (200). The acronym ERAD for ER-associated protein degradation was coined to describe degradation of misfolded proteins progressing in a reconstituted yeast system and requiring unidentified heat-labile cytosolic factors, ATP, and the chaperone calnexin (250). The identification in the mid 1990s of the 26S proteasome as the energy-consuming, heat-labile, and cytosolic factor (23, 153, 180, 315, 353, 403, 406, 410), and the involvement of ubiquitin-conjugating enzymes located in the cytosol (23, 153, 180, 315, 353, 403, 406, 410) led to the surprising conclusion that disposal of misfolded proteins synthesized in the ER lumen requires retro-translocation across the ER membrane into the cytosol.

Dislocation of aberrant proteins to the cytosol may involve Sec61, a proteinaceous channel that serves as the entry site for nascent polypeptides into the ER (179, 308, 310, 437). Exceptions are known such as substrates that may use the Sec61 homolog Ssh1p in Saccharomyces cerevisiae (165) as well as substrates whose retrotranslocation occurs independently of Sec61 (396) or even without involvement of a protein-conducting channel (310a). The derlins and signal peptide peptidase have also been recently implicated as putative components of a retrotranslocon (228, 229, 234, 287, 423, 424). With few exceptions [e.g., the dislocation of class I MHC triggered by the cytomegalovirus (CMV) immunoevasins US2 and US11 (410, 411)] retrotranslocation of ERAD candidates is inhibited upon proteasome inactivation, thus showing that retrotranslocation and degradation are coupled events (53, 222, 241, 249, 260, 264, 396).

4. Protein quality control in the ER: the unfolded versus misfolded conundrum

The ER lumen hosts an estimated 100 mg/ml proteins. Besides resident molecular chaperones and folding factors, thousands of different gene products (most of them displaying N-glycans) reside in the ER lumen for the time required to complete the folding program. This time may vary from a few minutes (e.g., 15 min for HA from the influenza virus) (60) to several hours [for gp160 glycoprotein from the HIV (225) or the blood coagulation protein factors V and VIII (309)]. Proteins that have completed the maturation program are rapidly released from the ER. Therefore, the vast majority of cargo present in the ER lumen is unstructured and/or exposes unfolded or misfolded determinants that elicit chaperone binding. Complex molecular mechanisms have evolved in eukaryotic cells to distinguish unstructured intermediates of the folding program that have to be preserved from degradation, from terminally misfolded proteins to be removed from the ER lumen. A simplistic view says that one solution selected by evolution to protect unstructured nascent chains synthesized in the ER lumen from unwanted destruction has been the positioning of the multisubunit complex responsible for protein degradation, the 26S proteasome, in the cytoplasm (206). This implies that folding-defective proteins must be actively trapped and extruded from the ER lumen before being exposed to the disposal machinery. It does not answer, however, a central question related to a crucial part of the protein quality control in the ER: how does the quality control machinery distinguish between folding polypeptides to be protected from degradation, native polypeptides to be released from the ER into the secretory line for transport to their final destination, and terminally misfolded proteins to be extracted from the folding machinery and transported into the cytoplasm for proteasome-mediated degradation (83, 256)?

The release of native proteins from the ER is the easiest to envision. Native proteins do not expose motifs (usually hydrophobic patches or unpaired cysteines) that elicit chaperone binding. This is a crucial difference with nonnative polypeptides, for which one mechanism for ER retention relies on association with resident chaperones that carry specific retrieval or retention sequences at their COOH termini that prevent forward transport (luminal KDEL-like sequences for soluble proteins or cytosolic KKXX-like extensions for membrane-bound proteins).

Recent findings show that protein secretion from the mammalian ER is energetically permissive (342) and that ER exit signals may lead to anterograde transport of misfolded polypeptides, at least in yeast (197). In the case of TTR variants (refer to sect. IIB1), as an example, the ER quality control machinery only prevents forward transport of the most highly destabilized structures but ignores others, disease-associated variants, in spite of compromised folding. This shows that nonnative proteins can induce formation of COPII vesicles at ER exit sites and be transported to the cell surface (127, 342) and may lead to a new definition of the ER quality control that takes into account folding energetics, independent of the acquisition or not of a native state.

Less evident is how the system distinguishes unfolded (defined as a polypeptide on its way to becoming a native molecule) from misfolded (defined as an irreparably unstructured protein to be rapidly removed from the folding compartment) because both conformers expose regions that attract ER-resident molecular chaperones. The regulation of these processes is better known for N-glycosylated proteins, and it is widely accepted that the oligosaccharide appendices and their processing by several ER-resident glucosidases, mannosidases, and one glucosyl-transferase play a crucial regulatory function in this recognition process (141).

5. A timer ticking in the ER lumen

Disposal of folding-defective proteins carrying N-glycans is one of the most thoroughly investigated aspects of protein degradation from the mammalian ER. It has been recently shown that protein degradation from the ER can start as soon as the ERAD candidate emerges in the lumen of the compartment when special "degrons" are displayed (381) or under conditions of ER overload (297). These are exceptions, rather than the rule. Normally, newly synthesized polypeptides are afforded a fair time window to explore conformational states that may eventually lead to the native structure. For proteins that will eventually be degraded, this is seen as a lag phase before degradation onset (268a). During the lag phase, N-glycosylated ERAD candidates remain trapped in the calnexin/calreticulin chaperone system and undergo formation and/or isomerization and/or reduction of intra- and intermolecular disulfide bonds in hopeless attempts to reach a conformation that fulfills ER quality control standards (264) (Fig. 2, steps 3a and 4a). A long-term retention of polypeptides in futile cycles of folding attempts would eventually interfere with the maturation of the vast array of newly synthesized polypeptides that enter the ER lumen at any given time. Changes in the mannose composition of the polypeptide-bound N-glycans are the key that determines the fate of the polypeptide. Removal of terminal mannoses could inhibit binding to calnexin and calreticulin and facilitate the association of folding-defective glycoproteins with ER-resident mannose-binding lectins and with BiP (262, 286) (Fig. 2, step 3b). Consistently, substrate cycling in the calnexin chaperone system and lag phase preceding degradation onset are prolonged by preservation of the Man₉ configuration (69, 264, 420). The finding that inhibition of mannose removal from N-glycans protects folding-defective polypeptides from ERAD (359) led to the concept of mannose timer (41, 144), proposing that progressive protein demannosylation terminates the maturation phase and initiates a series of events, still incompletely characterized, that eventually lead to retrotranslocation of the terminally misfolded polypeptide into the cytosol for ERAD (Fig. 2, steps 4b).

6. Protein demannosylation in the ER lumen

Accumulating evidence highlights the crucial role of kifunensine-sensitive 1,2-mannosidase(s) in timing glycoprotein degradation from the ER (41, 141, 145, 148, 219, 268a, 291a). In S. cerevisiae, removal of a single mannose residue from the central branch B of the oligosaccharide displayed by folding-defective polypeptides (Fig. 1) initiates a series of events eventually leading to retrotranslocation and disposal. The glycanase involved in removal of this specific mannose residue is the MnsI (174). The corresponding mammalian enzyme, the ER -mannosidase I, shows the same specificity for the mannose residue B (273).

It appears unlikely that the strength of the signal obtained by removal of the terminal B branch mannose residue is the same in the yeast and in the mammalian cell. In higher eukaryotes, in fact, substrate cycling in the calnexin chaperone system offers good protection from disposal, and removal of mannose B is not sufficient to abolish it (141, 219, 274). Irreversible extraction of folding-defective glycopolypeptides from the calnexin system is only obtained upon removal of the mannose on branch A, the sole residue of the protein-bound oligosaccharide that can be reglucosylated by the GT1. Consistently, it has been shown that extensive N-glycan processing to Man_5–6 configurations precedes or elicits disposal from the mammalian ER (87, 99–101, 159, 198). Moreover, removal of 1,2-linked mannose is required for degradation of misfolded proteins expressed in mannosyl-phosphoryl-dolichol-deficient cell lines [e.g., B3F7 and MadIA214 (87, 290)] that do not have a cleavable mannose on branch B but display a cleavable terminal mannose on branch A (Fig. 1).

Other advantages of extensive demannosylation are that oligosaccharides lacking branch A cannot bind to ERGIC53/UIP36 cargo receptors (Fig. 2) and that the overall polypeptide volume is reduced, thus facilitating the transit of ERAD candidates across the ER membrane through the proteinaceous channel. The identity of the glycanase(s) that perform the extensive mannose trimming observed during preparation of the folding-defective polypeptides for proteasomal disposal is still a matter of debate and extensive research because data show that the ER -mannosidase I can proceed with removal of mannoses on branches A and C only at unphysiological conditions (149). At least three possibilities exist: 1) the ERAD substrate and ER -mannosidase I are segregated to a specialized subregion of the ER (101, 164) where the mannosidase concentration reaches levels similar to those shown in vitro to cause extensive mannose removal (149, 420), 2) intervention of Golgi endomannosidase(s) that cleaves A branch mannoses, or 3) intervention of a new class of recently characterized mannosidase-like proteins, EDEM1, EDEM2, and EDEM3 (155, 246, 262, 286, 290, 291, 291a).

7. The EDEM triad as ERAD regulator

The glycosylhydrolase family 47 (GH47; Refs. 147, 274, 291a; Fig. 5) comprises three subfamilies including the ER 1,2-mannosidase I (ERManI), three Golgi 1,2-mannosidases (GolgiManIA, IB, and IC), and three EDEM proteins [EDEM1, for ER degradation enhancing -mannosidase-like protein (160), EDEM2, and EDEM3 (246, 291)]. EDEM proteins are major targets of the ER-stress-induced Ire1/Xbp1 pathway (155, 291, 427). Mammalian cells use this pathway to enhance their capacity for ERAD in response to an increase in cargo load and/or accumulation of misfolded polypeptides (291, 427, 428). RNA interference directed against EDEM proteins (119, 262), and inactivation of the Ire1/Xbp1 pathway that regulates their intraluminal level (427), both reduce ERAD efficiency. Suboptimal ERAD activity eventually inhibits protein folding and reduces secretory capacity, thus revealing important cross-talk between the folding and ERAD pathways (86, 427).

View larger version (14K): [in this window] [in a new window]   FIG. 5. The members of the glycosyl hydrolase 47 family. Members of this family cleave terminal 1,2-mannoses (refer to Fig. 1). Numbers show the length of the mannosidase homology domain (red box) and the length of the proteins, respectively. EDEMs are soluble proteins. Only EDEM3 contains a conventional ER-retrieval sequence (KDEL) and a protease-associated (PA) domain. ER and Golgi mannosidases are type II membrane proteins (the membrane anchor is shown as a black box).

How upregulation of EDEM proteins actually facilitates the degradation of folding-defective glycopolypeptides (262, 286) is not fully understood. Recent evidence suggests that EDEM1 (290) and EDEM3 (155) levels determine the rate of ERAD substrate demannosylation (see below). EDEMs may also work as classical chaperones by preventing the formation of disulfide-bonded dimers (161) or covalent aggregates (290) containing terminally misfolded glycoproteins released from calnexin. Inhibition of aggregation seems essential to facilitate disposal of misfolded glycoproteins released from calnexin. Current models claim, in fact, that dislocation across the ER membrane occurs through a narrow proteinaceous channel, even though one report shows that in the US2/US11-modified cells unfolding of the ERAD candidate is not required for retrotranslocation (94, 310a, 370). The chaperone-like activity of EDEM is independent from the capacity to accelerate substrate demannosylation. In fact, overexpression of inactive mutants of EDEM1 still inhibit protein aggregation enhancing substrate degradation (290).

Despite conservation of the ()₇ barrel catalytic domain of class I mannosidases, EDEM1 was originally described as a putative lectin, rather than an active mannosidase because it lacks a specific disulfide bond conserved in mannosidases (160). However, it was uncovered more recently that the disulfide absent in the EDEM proteins is not conserved among all mannosidases and is, in any case, dispensable for glycanase activity (274). Moreover, despite the relatively low level of sequence identity (35%), EDEM proteins conserve all catalytic residues required for glycolytic activity and for binding of the specific inhibitor of 1,2 mannosidases kifunensine, and structural modeling indicates no difference in their location (160, 189, 190, 368). Interestingly, increase of the intraluminal level of EDEM1 (290) and EDEM3 (155) substantially accelerates demannosylation of folding-defective polypeptides. Although the formal proof of enzymatic activity assessed with purified components in vitro is still missing, for both EDEM1 (290) and EDEM3 (155), substitution of a conserved catalytic residue (E220Q and E147Q for EDEM1 and -3, respectively) abolished enhancement of substrate demannosylation upon elevation of the intraluminal level. Acceleration of mannose removal upon upregulation of EDEM1 also occurs in B3F7 cells, which are characterized by the addition of aberrant oligosaccharides to nascent polypeptide chains that lack mannoses on both their B and C branches (Fig. 1) (290). Thus EDEM1 (and possibly EDEM2 and EDEM3) enhances removal of the terminal branch A mannose, the only cleavable terminal mannose present in glycoproteins in this cell line and the only saccharide that can be reglucosylated by GT1 to prolong retention of folding-defective polypeptides in the calnexin cycle (290).

8. Cytosolic lectins prepare ERAD candidates for destruction

N-glycans serve as degradation tags even after release of ERAD candidates into the cytosol. Most misfolded proteins in the cytoplasm including those arriving from the ER are decorated with polyubiquitin chains to promote degradation by the 26S proteasome. Polyubiquitylation occurs by the concerted action of activating E1, conjugating E2, and ligating E3 enzymes located in the cytosol (150). Several E3 variants exist, and one of the best characterized E3 complexes, the SCF (for Skp1, Cul1, Roc1), contains a Fbs1 (F-box sugar recognition) protein in the adult brain and testis or a more ubiquitously expressed Fbs2 protein that confers specificity for glycosylated proteins arriving in the cytosol from the ER (429, 430). Interestingly, Fbs1 can independently act as a monomer or as a Fbs1-Skp1 heterodimer to facilitate degradation of misfolded glycoproteins by acting as a mannose-binding lectin chaperone that suppresses aggregate formation (431). This dual function of the cytosolic Fbs1 (polyubiquitylation + lectin) mirrors the dual function of EDEM family members in the ER lumen. EDEM proteins, in fact, facilitate disposal of glycoproteins from the ER operating in two independent ways, namely, accelerating mannose removal and preventing aggregation of terminally misfolded glycoproteins released from calnexin (161, 290). N-glycans are eventually removed from ERAD candidates by cytosolic PNG1 (156, 362). While the removal of glycans facilitates degradation by the proteasome, it is not absolutely required (260).

9. Viral gene products to assess mechanisms of ERAD

A long-lasting coevolution with the hosts led viruses to learn how to make good use of several cellular mechanisms. As described in the previous sections, several model viral proteins have been employed to unravel different aspects of cellular protein biogenesis. An increasing amount of data are now available on how viruses co-opt the ERAD machinery. As an example, the US2 and US11 gene products of the CMV are localized to the ER lumen of infected cells and trigger the rapid retro-translocation into the cytosol and destruction by the proteasome of class I MHC molecules (410, 411). This prevents cell surface expression of viral antigens that could activate immunosurveillance by the host cell (124). Cells expressing US2 and US11 have been used to identify several membrane-bound and cytosolic components involved in mammalian ERAD. Sec61 (410, 411) and/or Derlin1 and Derlin2 (228, 424) have been identified as potential components of proteinaceous channel(s) proposed to be used for retro-translocation of ERAD substrates from the ER lumen into the cytosol. The signal peptide peptidase also appears to be an essential component (with unknown function) of US2 (but not US11) class I MHC retrotranslocation (234), and Sel1L (an ortholog of the yeast Hrd3p) is involved in the same process catalyzed by US11 (but not US2) (275). Finally, VIMP, a transmembrane protein that recruits the p97/Cdc48 AAA ATPase and ubiquitin ligases, acts as part of the extraction machinery complex engaged by the heavy chain for degradation (181, 229, 422, 423).

Class I MHC destruction triggered by US2 differs mechanistically from destruction of the same substrate triggered by US11 (105, 138, 228, 234), and both have similarities, as well as striking differences with ERAD of misfolded cellular glycoproteins. As an example, they completely bypass the ER lectins and ER-resident sugar-processing enzymes that play essential roles in substrate selection for protein quality control in noninfected cells. In addition, they apparently do not require unfolding of the ERAD candidate for retrotranslocation (94, 310a, 370). They also are able to uncouple retrotranslocation and degradation, two tightly coupled events for most cellular substrates that normally accumulate in the ER lumen upon proteasome inactivation (53, 222, 241, 249, 260, 264, 396). It still remains unclear to which extent the mechanisms activated by the CMV immunoevasins contribute to the degradation of cellular proteins in noninfected cells, but it is evident that one of the challenges for the future is to understand and characterize all cellular component regulating disposal of folding-defective polypeptides.

10. Alternative degradation pathways

The disposal of misfolded proteins from the ER lumen is normally delayed and not fully prevented upon inhibition of the 26S proteasome. Surrogate degradative systems appear to intervene in the absence of proteasome activity. One example is the giant protease tripeptidyl peptidase II (TPPII), which shows enhanced activity in proteasome-inhibitor adapted cells (111, 117). In addition, recent data suggest that at least upon acute nutrient deprivation for some misfolded proteins produced in the ER lumen [e.g., the mutant 1-antitrypsin Z protein (186, 211) and fibrinogen (212)], disposal could involve a completely distinct mechanism named autophagocytosis or autophagy (321). This is a major intracellular degradation pathway characterized by bulk sequestration of cytoplasmic constituents within a double-membrane-bound vesicle and subsequent fusion with lysosomes (202). It has been suggested that autophagic degradation may be important for clearance of ubiquitylated protein aggregates (204), thus of aberrant species that are not attacked by proteasomes and may actually cause their inactivation (20). Certainly, autophagy maintains cellular homeostasis, and its inactivation results in intracellular accumulation of protein aggregates leading to neurodegeneration even in the absence of mutant or folding-defective proteins (135).

As a final consideration, in some cases, aberrant substrates may form detergent-insoluble deposits, thus escaping immunoisolation and detection upon proteasome inhibition (363). This can be, and has been, erroneously interpreted as degradation of the substrate performed by alternative ER-resident or cytosolic degradation machineries that cannot be inhibited by conventional protease inhibitor cocktails.

11. ERAD in yeast compared with higher eukaryotes

Many aspects of protein disposal from the yeast ER are conserved in metazoans. In both systems, most folding-incompetent polypeptides must be extracted from the folding machinery and cross the ER membrane to be degraded by cytosolic proteasomes. Due to the facility of manipulating the yeast genome (418), many aspects of ERAD and several factors regulating the processes have been discovered in the yeast S. cerevisiae. For some of them, e.g., the recently identified ER lectin Yos9p, which is part of the multimeric Hrd1p complex comprising Kar2p (the yeast BiP) and several membrane-embedded and cytosolic proteins involved in retrotranslocation and ubiquitination of ERAD substrates (reviewed in Refs. 172, 418), functional mammalian homologs have not yet been identified. Also, the specific machineries involved in the detection of structural protein defects [the ERAD-L (or Hrd1p complex) to inspect luminal defects, the ERAD-C (or Doa10p complex) for cytosolic ones, and the ERAD-M for structural defects in the transmembrane regions of newly synthesized polypeptides] have been characterized in yeast (1, 46, 71, 109, 165, 172, 283, 388) but are poorly known in higher eukaryotes. Whereas ERAD-M and ERAD-C substrates are proposed to be targeted directly for retrotranslocation, ERAD-L substrates in yeast first traffic to the Golgi before returning to the ER for subsequent retrotranslocation and proteasomal degradation (388), a trafficking pathway that has no clear counterpart in mammalian ERAD.

Significantly, even homologous proteins may participate in processes that are mechanistically different in yeast and mammalian quality control. In mammalian cells, a "hands off" of folding-defective polypeptides from calnexin to the BiP chaperone system has been shown, and substrate release from the calnexin/calreticulin cycle initiates the degradation process (18, 40, 69, 76, 184, 203, 263–265, 354, 363, 420). Although several components of the lectin chaperone system (chaperones and sugar-processing enzymes) have ortholog proteins in yeast, the differences between the two systems are striking (also refer to sect. IIC6). To summarize some of them, 1) calreticulin is absent from S. cerevisiae and calnexin lacks a cytosolic tail; therefore, it is unable to directly interact with cytosolic components. 2) Calnexin (250) and glucose trimming (157, 175) are required for ERAD in lower eukaryotes, whilst in mammalian cells, both calnexin and calreticulin are dispensable for ERAD and substrate association with them actually delays disposal. Moreover, it is undisputed that inhibition of glucose removal that results in a bypass of the calnexin cycle substantially accelerates onset of protein degradation in mammalian cells (14, 52, 69, 139, 191, 192, 264, 270). 3) S. cerevisiae lacks a functional homolog of GT1 (92) that in mammals prolongs retention of folding-defective polypeptides in the protective calnexin/ERp57 folding cage. Interestingly, Schizosaccharomyces pombe possesses GT so these processes can also vary among the various yeast strains (91). 4) The mammalian ER contains at least four members of the glycosyl hydrolase 47 family (ER -mannosidase I, EDEM1, EDEM2, and EDEM3) and supports extensive demannosylation of folding-defective polypeptides. The yeast ER only contains orthologs of the ER -mannosidase I and of EDEM1, and removal of a single mannose from branch B seems to be sufficient to elicit polypeptide removal from the ER lumen.

	III. CONFORMATIONAL AND ENDOPLASMIC RETICULUM STORAGE DISEASES

Top Previous Next References

 
A. Human Diseases Caused by Defective Protein Folding or Trafficking: Selected Examples

Secretory and membrane proteins begin their maturation in the ER where they fold, oligomerize, and are frequently subjected to covalent modifications to become biologically active. To exit the ER and be transported to their site of activity, newly synthesized proteins must pass a tightly controlled quality control test and some proteins must expose cytosolic and luminal signals for forward transport (83). Proteins that fail to do so are rerouted to the cytosol for degradation. It is important to understand the molecular mechanisms that coordinate protein synthesis, folding, transport and degradation because unbalances in these processes are at the basis of many human diseases (Tables 5–7) (thoroughly reviewed in Refs. 10–12, 268a).

Inclusion body myopathies are associated with severe weakness caused by muscle cells accumulating cytoplasmic aggregates. In the case of Paget's disease, intracellular accumulation of aggregates is caused by missense mutations of the p97/Cdc48/VCP gene (404) that affect the capacity of cells to degrade misfolded proteins, especially those delivered into the cytosol from the ER lumen. p97 is in fact one coordinator of a complex machinery comprising ubiquitin ligases gp78 and Ufd2, deubiquitinating enzymes VCIP135, and ataxin3 that regulates access of misfolded proteins to the proteasome chambers (404).

The polycystic liver disease is the last selected example presented here. This is an interesting pathological state, in most cases asymptomatic, but that can degenerate in sudden abdominal pain upon cystic rupture. Polycystic liver disease is caused by aberrant cotranslational protein processing associated with mutations in the Sec63 translocon and in the regulatory (-subunit) of the glucosidase II (79). All pathogenic variants of the glucosidase II -subunit result in premature termination of translation and loss of the polypeptide COOH-terminal containing the ER retention motif and the sequences required for formation of the functional heterodimeric complex with the glucosidase II -subunit.

A variety of congenital defects are associated with ER storage diseases caused by protein misfolding in the ER. The source of these mutations can be found in the secretory cargo leading to its degradation or creation of a toxic aberrant by-product that disrupts the strictly regulated ER environment. Alternatively, defects in the secretory machinery can also adversely affect the cargo that is most dependent on their activity for proper maturation. In the end, both types of defects result in the destruction of misfolded proteins supporting the loss of their cellular activity or their accumulation in the ER as a toxic end product.

B. Pharmacological and Chemical Chaperones to Rescue Structurally Defective, Functional Proteins

Several inherited human diseases are caused by mutations in the sequence of specific proteins leading to folding defects that in several cases do not affect the activity of the protein. Rather, they significantly slow the polypeptide folding and result in a disposal of the mutated polypeptide chain which is elicited before acquisition of the native, transport-competent architecture (268a). This premature destruction causes the debilitating loss-of-function syndromes. Examples of this category of diseases include cystic fibrosis, Fabry disease, and nephrogenic diabetes insipidus (Table 5). In these cases, therapeutic approaches based on the use of chemical or pharmacological chaperones (21, 268a) can be envisioned, that promote and/or accelerate productive folding and inhibit ER retention, thus facilitating the transport of the polypeptide to its site of action.

One indication that the folding defect of the mutant protein may be reverted by the use of chemical chaperones is the increase of the polypeptide folding efficiency upon expression at lower temperature (72, 195). Another is the increase in the export of the select functional polypeptide from the ER upon inhibition of ERAD (392) as the folding and degradation processes are for many proteins in kinetic competition (268a).

Chemical compounds with proven effect in the stabilization of mutant proteins and/or in the facilitation of transport of mutant proteins at the site of activity include 4-phenyl butyrate (PBA), glycerol, trimethylamine N-oxide, dimethyl sulfoxide, deuterated water (35), and derivatives of bile acids such as ursodeoxycholic acid (298, 421). Chemical chaperones improve folding capacity by nonspecific mechanisms and require high dosages. Therefore, they often are of limited therapeutic value. However, there is at least one example of a chemical chaperone, PBA, that has been approved by the United States Food and Drug Administration for clinical use. In animal models for type 2 diabetes mellitus (298) or for 1-antitrypsin deficiency (37), PBA has been shown to alleviate the disease state. The mechanism of action of PBA is unclear, but its capacity to alleviate ER stress and facilitate secretion of the disease-related, mutated proteins may be related to its activity as a chaperone that efficiently inhibits protein aggregation (213). In any case, studies with chemical chaperones offered an important proof of principle and paved the way for characterization of several, substrate-specific pharmacological chaperones that proved efficient in cultured cells or that have already been used in animal and/or clinical trials (22, 58, 232, 271). Here are a few selected examples: V2 receptor antagonists rescued mutant vasopressin receptor from proteasomal degradation (272); gonadotropin-releasing hormone (GnRH) peptidomimetics rescued secretion of several GnRH mutants (177); the cromophore retinal rescued maturation of mutant opsin (285); specific inhibitors facilitated maturation and transport of mutant voltage-gated potassium channels (93), beta-glucocerebrosidase (334), and -D-galactosidase (90); copper supplementation alleviated maturation defects of the mutant copper transporting ATPase (195); and 4-phenylbutyrate corrected folding defects of several cystic fibrosis channel mutations (434).

	IV. CONCLUDING REMARKS

Top Previous Next References

 
The ER contains a variety of dedicated chaperone systems, protein modifiers, and protein processors that aid in the maturation of the large number of proteins that traverse the eukaryotic secretory pathway. In recent years, our understanding of the protein maturation process in the ER has become much clearer. Studies have provided evidence for the necessity and the extensiveness of the initial cotranslational and cotranslocational events. During its time of translation, a protein has already been seen and worked on by some 30 polypeptide chains ensuring that the protein gets off to a good start in a tightly regulated translocon-associated environment. This assistance continues posttranslationally until the properly folded protein leaves the ER. A quality control system is also in place that monitors the fidelity of the maturation process, retaining misfolded proteins in the ER and efficiently targeting the terminally misfolded for degradation.

N-linked glycans are employed as both maturation and quality control tags that dictate which proteins should be recruited to interact with the nascent chain. Large advances have been made in translating the glyco-code of the ER or what a given glycan composition means. What does it tell us about the protein's status (folded, unassembled, or terminally misfolded)? What proteins recognize the given glycan composition (chaperones, quality control, or sorting receptors)? What do they do with the glycoprotein once they bind to their specific glycan signal (assist folding or target the protein for destruction)?

Since a source of a large number of human disease states is defects in the protein folding and maturation, a more thorough knowledge of these processes is essential. This will allow us to compare the maturation of normal and aberrant proteins to see where they deviate and possibly provide insight into how they can be rerouted to stay on the normal pathway.

	GRANTS

Top Previous Next References

 
M. Molinari is supported by grants from the Max Cloetta Foundation, Foundation for Research on Neurodegenerative Diseases, Swiss National Center of Competence in Research on Neural Plasticity and Repair, Swiss National Science Foundation, Synapsis Foundation, Bangerter-Rhyner Foundation Aetas, and Telethon. D. N. Hebert is supported by United States Public Health Service Grant CA-79864.

	ACKNOWLEDGMENTS

Top References

 
Address for reprint requests and other correspondence: M. Molinari, Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland (e-mail: maurizio.molinari@irb.unisi.ch); D. N. Hebert, Univ. of Massachusetts, Amherst, MA 01003 (e-mail: dhebert@biochem.umass.edu).

	REFERENCES

Top

 

1. Ahner A, Brodsky JL. Checkpoints in ER-associated degradation: excuse me, which way to the proteasome? Trends Cell Biol 14: 474–478, 2004.[CrossRef][Web of Science][Medline]
2. Alder NN, Shen Y, Brodsky JL, Hendershot LM, Johnson AE. The molecular mechanisms underlying BiP-mediated gating of the Sec61 translocon of the endoplasmic reticulum. J Cell Biol 168: 389–399, 2005.[Abstract/Free Full Text]
3. Andersson H, Nilsson I, von Heijne G. Calnexin can interact with N-linked glycans located close to the endoplasmic reticulum membrane. FEBS Lett 397: 321–324, 1996.[CrossRef][Web of Science][Medline]
4. Anelli T, Alessio M, Mezghrani A, Simmen T, Talamo F, Bachi A, Sitia R. ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family. EMBO J 21: 835–844, 2002.[CrossRef][Web of Science][Medline]
5. Anfinsen CB. Principles that govern the folding of protein chains. Science 181: 223–230, 1973.[Free Full Text]
6. Anfinsen CB, Haber E. Studies on the reduction and re-formation of protein disulfide bonds. J Biol Chem 236: 1361–1363, 1961.[Free Full Text]
7. Anfinsen CB, Haber E, Sela M, White FH Jr. The kinetics of formation of native ribonuclease during oxidation of the reduced polypeptide chain. Proc Natl Acad Sci USA 47: 1309–1314, 1961.[Free Full Text]
8. Anttonen AK, Mahjneh I, Hamalainen RH, Lagier-Tourenne C, Kopra O, Waris L, Anttonen M, Joensuu T, Kalimo H, Paetau A, Tranebjaerg L, Chaigne D, Koenig M, Eeg-Olofsson O, Udd B, Somer M, Somer H, Lehesjoki AE. The gene disrupted in Marinesco-Sjogren syndrome encodes SIL1, an HSPA5 cochaperone. Nat Genet 37: 1309–1311, 2005.[CrossRef][Web of Science][Medline]
9. Argon Y, Simen BB. GRP94, an ER chaperone with protein and peptide binding properties. Semin Cell Dev Biol 10: 495–505, 1999.[CrossRef][Web of Science][Medline]
10. Aridor M, Balch WE. Integration of endoplasmic reticulum signaling in health and disease. Nat Med 5: 745–751, 1999.[CrossRef][Web of Science][Medline]
11. Aridor M, Hannan LA. Traffic jam: a compendium of human diseases that affect intracellular transport processes. Traffic 1: 836–851, 2000.[CrossRef][Web of Science][Medline]
12. Aridor M, Hannan LA. Traffic jams II: an update of diseases of intracellular transport. Traffic 3: 781–790, 2002.[CrossRef][Web of Science][Medline]
13. Arunachalam B, Cresswell P. Molecular requirements for the interaction of class II major histocompatibility complex molecules and invariant chain with calnexin. J Biol Chem 270: 2784–2790, 1995.[Abstract/Free Full Text]
14. Ayalon-Soffer M, Shenkman M, Lederkremer GZ. Differential role of mannose and glucose trimming in the ER degradation of asialoglycoprotein receptor subunits. J Cell Sci 112: 3309–3318, 1999.[Abstract]
15. Ban N, Nissen P, Hansen J, Moore PB, Steitz TA. The complete atomic structure of the large ribosomal subunit at 2.4 A resolution. Science 289: 905–920, 2000.[Abstract/Free Full Text]
16. Baryshev M, Sargsyan E, Mkrtchian S. ERp29 is an essential endoplasmic reticulum factor regulating secretion of thyroglobulin. Biochem Biophys Res Commun 340: 617–624, 2006.[CrossRef][Web of Science][Medline]
17. Bause E. Structural requirements of N-linked-glycosylation of proteins. Biochem J 209: 331–336, 1983.[Web of Science][Medline]
18. Beggah A, Mathews P, Beguin P, Geering K. Degradation and endoplasmic reticulum retention of unassembled alpha- and beta-subunits of Na,K-ATPase correlate with interaction of BiP. J Biol Chem 271: 20895–20902, 1996.[Abstract/Free Full Text]
19. Ben-Arieh SV, Zimerman B, Smorodinsky NI, Yaacubovicz M, Schechter C, Bacik I, Gibbs J, Bennink JR, Yewdell JW, Coligan JE, Firat H, Lemonnier F, Ehrlich R. Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J Virol 75: 10557–10562, 2001.[Abstract/Free Full Text]
20. Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292: 1552–1555, 2001.[Abstract/Free Full Text]
21. Bernier V, Bichet DG, Bouvier M. Pharmacological chaperone action on G-protein-coupled receptors. Curr Opin Pharmacol 4: 528–533, 2004.[CrossRef][Web of Science][Medline]
22. Bernier V, Lagace M, Bichet DG, Bouvier M. Pharmacological chaperones: potential treatment for conformational diseases. Trends Endocrinol Metab 15: 222–228, 2004.[CrossRef][Web of Science][Medline]
23. Biederer T, Volkwein C, Sommer T. Degradation of subunits of the Sec61p complex, an integral component of the ER membrane, by the ubiquitin-proteasome pathway. EMBO J 15: 2069–2076, 1996.[Web of Science][Medline]
24. Bies C, Guth S, Janoschek K, Nastainczyk W, Volkmer J, Zimmermann R. A Scj1p homolog and folding catalysts present in dog pancreas microsomes. Biol Chem 380: 1175–1182, 1999.[CrossRef][Web of Science][Medline]
25. Blobel G, Dobberstein B. Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. J Cell Biol 67: 835–851, 1975.[Abstract/Free Full Text]
26. Blobel G, Sabatini DD. Ribosome-membrane interaction in eukaryotic cells. Biomembranes 2: 193–195, 1971.
27. Blond Elguindi S, Cwirla SE, Dower WJ, Lipshutz RJ, Sprang SR, Sambrook JF, Gething MJ. Affinity panning of a library of peptides displayed on bacteriophages reveals the binding specificity of BiP. Cell 75: 717–728, 1993.[CrossRef][Web of Science][Medline]
28. Bornstein SR, Tajima T, Eisenhofer G, Haidan A, Aguilera G. Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice. FASEB J 13: 1185–1194, 1999.[Abstract/Free Full Text]
29. Bourdi M, Demady D, Martin JL, Jabbour SK, Martin BM, George JW, Pohl LR. cDNA cloning and baculovirus expression of the human liver endoplasmic reticulum P58: characterization as a protein disulfide isomerase isoform, but not as a protease or a carnitine acyltransferase. Arch Biochem Biophys 323: 397–403, 1995.[CrossRef][Web of Science][Medline]
30. Braakman I, Hoover-Litty H, Wagner KR, Helenius A. Folding of influenza hemagglutinin in the endoplasmic reticulum. J Cell Biol 114: 401–411, 1991.[Abstract/Free Full Text]
31. Branza-Nichita N, Negroiu G, Petrescu AJ, Garman EF, Platt FM, Wormald MR, Dwek RA, Petrescu SM. Mutations at critical N-glycosylation sites reduce tyrosinase activity by altering folding and quality control. J Biol Chem 275: 8169–8175, 2000.[Abstract/Free Full Text]
32. Breakefield XO, Kamm C, Hanson PI. TorsinA: movement at many levels. Neuron 31: 9–12, 2001.[CrossRef][Web of Science][Medline]
33. Brennan SO, Wyatt J, Medicina D, Callea F, George PM. Fibrinogen brescia: hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a gamma284 GlyArg mutation. Am J Pathol 157: 189–196, 2000.[Abstract/Free Full Text]
34. Brightman SE, Blatch GL, Zetter BR. Isolation of a mouse cDNA encoding MTJ1, a new murine member of the DnaJ family of proteins. Gene 153: 249–254, 1995.[CrossRef][Web of Science][Medline]
35. Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS, Welch WJ. Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones 1: 117–125, 1996.[CrossRef][Web of Science][Medline]
36. Bu G. The roles of receptor-associated protein (RAP) as a molecular chaperone for members of the LDL receptor family. Int Rev Cytol 209: 79–116, 2001.[Web of Science][Medline]
37. Burrows JA, Willis LK, Perlmutter DH. Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci USA 97: 1796–1801, 2000.[Abstract/Free Full Text]
38. Busca R, Martinez M, Vilella E, Peinado J, Gelpi JL, Deeb S, Auwerx J, Reina M, Vilaro S. The carboxy-terminal region of human lipoprotein lipase is necessary for its exit from the endoplasmic reticulum. J Lipid Res 39: 821–833, 1998.[Abstract/Free Full Text]
39. Bush KT, Hendrickson BA, Nigam SK. Induction of the FK506-binding protein, FKBP13, under conditions which misfold proteins in the endoplasmic reticulum. Biochem J 303: 705–708, 1994.[Web of Science][Medline]
40. Cabral CM, Liu Y, Moremen KW, Sifers RN. Organizational diversity among distinct glycoprotein endoplasmic reticulum-associated degradation programs. Mol Biol Cell 13: 2639–2650, 2002.[Abstract/Free Full Text]
41. Cabral CM, Liu Y, Sifers RN. Dissecting glycoprotein quality control in the secretory pathway. Trends Biochem Sci 26: 619–624, 2001.[CrossRef][Web of Science][Medline]
42. Cai H, Wang CC, Tsou CL. Chaperone-like activity of protein disulfide isomerase in the refolding of a protein with no disulfide bonds. J Biol Chem 269: 24550–24552, 1994.[Abstract/Free Full Text]
43. Caramelo JJ, Castro OA, Alonso LG, De Prat-Gay G, Parodi AJ. UDP-Glc:glycoprotein glucosyltransferase recognizes structured and solvent accessible hydrophobic patches in molten globule-like folding intermediates. Proc Natl Acad Sci USA 100: 86–91, 2003.[Abstract/Free Full Text]
44. Caramelo JJ, Castro OA, de Prat-Gay G, Parodi AJ. The endoplasmic reticulum glucosyltransferase recognizes nearly native glycoprotein folding intermediates. J Biol Chem 279: 46280–46285, 2004.[Abstract/Free Full Text]
45. Carreno BM, Screiber KL, McKean DJ, Stroynowski I, Hansen TH. Aglycosylated and phosphatidylinositol-anchored MHC class I molecules are associated with calnexin. Evidence implicating the class I-connecting peptide segment in calnexin association. J Immunol 154: 5173–5180, 1995.[Abstract]
46. Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126: 361–373, 2006.[CrossRef][Web of Science][Medline]
47. Chavan M, Chen Z, Li G, Schindelin H, Lennarz WJ, Li H. Dimeric organization of the yeast oligosaccharyl transferase complex. Proc Natl Acad Sci USA 103: 8947–8952, 2006.[Abstract/Free Full Text]
48. Chen W, Helenius A. Role of ribosome and translocon complex during folding of influenza hemagglutinin in the endoplasmic reticulum of living cells. Mol Biol Cell 11: 765–772, 2000.[Abstract/Free Full Text]
49. Chen W, Helenius J, Braakman I, Helenius A. Cotranslational folding and calnexin binding during glycoprotein synthesis. Proc Natl Acad Sci USA 92: 6229–6233, 1995.[Abstract/Free Full Text]
50. Chevalier M, Rhee H, Elguindi EC, Blond SY. Interaction of murine BiP/GRP78 with the DnaJ homologue MTJ1. J Biol Chem 275: 19620–19627, 2000.[Abstract/Free Full Text]
51. Chevet E, Wong HN, Gerber D, Cochet C, Fazel A, Cameron PH, Gushue JN, Thomas DY, Bergeron JJ. Phosphorylation by CK2 and MAPK enhances calnexin association with ribosomes. EMBO J 18: 3655–3666, 1999.[CrossRef][Web of Science][Medline]
52. Chillaron J, Adan C, Haas IG. Mannosidase action, independent of glucose trimming, is essential for proteasome-mediated degradation of unassembled glycosylated Ig light chains. Biol Chem 381: 1155–1164, 2000.[CrossRef][Web of Science][Medline]
53. Chillaron J, Haas IG. Dissociation from BiP and retrotranslocation of unassembled immunoglobulin light chains are tightly coupled to proteasome activity. Mol Biol Cell 11: 217–226, 2000.[Abstract/Free Full Text]
54. Chin DJ, Gil G, Faust JR, Goldstein JL, Brown MS, Luskey KL. Sterols accelerate degradation of hamster 3-hydroxy-3-methylglutaryl coenzyme A reductase encoded by a constitutively expressed cDNA. Mol Cell Biol 5: 634–641, 1985.[Abstract/Free Full Text]
55. Christensen JH, Siggaard C, Corydon TJ, Robertson GL, Gregersen N, Bolund L, Rittig S. Impaired trafficking of mutated AVP prohormone in cells expressing rare disease genes causing autosomal dominant familial neurohypophyseal diabetes insipidus. Clin Endocrinol 60: 125–136, 2004.[CrossRef][Medline]
56. Chung KT, Shen Y, Hendershot LM. BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J Biol Chem 277: 47557–47563, 2002.[Abstract/Free Full Text]
57. Cochella L, Green R. Fidelity in protein synthesis. Curr Biol 15: R536–R540, 2005.[CrossRef][Web of Science][Medline]
58. Cohen FE, Kelly JW. Therapeutic approaches to protein-misfolding diseases. Nature 426: 905–909, 2003.[CrossRef][Medline]
59. Cooper AA, Gitler AD, Cashikar A, Haynes CM, Hill KJ, Bhullar B, Liu K, Xu K, Strathearn KE, Liu F, Cao S, Caldwell KA, Caldwell GA, Marsischky G, Kolodner RD, Labaer J, Rochet JC, Bonini NM, Lindquist S. -Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313: 324–328, 2006.[Abstract/Free Full Text]
60. Copeland CS, Doms RW, Bolzau EM, Webster RG, Helenius A. Assembly of influenza hemagglutinin trimers and its role in intracellular transport. J Cell Biol 103: 1179–1191, 1986.[Abstract/Free Full Text]
61. Cunnea PM, Miranda-Vizuete A, Bertoli G, Simmen T, Damdimopoulos AE, Hermann S, Leinonen S, Huikko MP, Gustafsson JA, Sitia R, Spyrou G. ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress. J Biol Chem 278: 1059–1066, 2003.[Abstract/Free Full Text]
62. Daniels R, Kurowski B, Johnson AE, Hebert DN. N-linked glycans direct the cotranslational folding pathway of influenza hemagglutinin. Mol Cell 11: 79–90, 2003.[CrossRef][Web of Science][Medline]
63. Danilczyk UG, Williams DB. The lectin chaperone calnexin utilizes polypeptide-based interactions to associate with many of its substrates in vivo. J Biol Chem 276: 25532–25540, 2001.[Abstract/Free Full Text]
64. Davila S, Furu L, Gharavi AG, Tian X, Onoe T, Qian Q, Li A, Cai Y, Kamath PS, King BF, Azurmendi PJ, Tahvanainen P, Kaariainen H, Hockerstedt K, Devuyst O, Pirson Y, Martin RS, Lifton RP, Tahvanainen E, Torres VE, Somlo S. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat Genet 36: 575–577, 2004.[CrossRef][Web of Science][Medline]
65. Davis EC, Broekelmann TJ, Ozawa Y, Mecham RP. Identification of tropoelastin as a ligand for the 65-kD FK506-binding protein, FKBP65, in the secretory pathway. J Cell Biol 140: 295–303, 1998.[Abstract/Free Full Text]
66. De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Ellisman MH, Taylor P. A mutation linked with autism reveals a common mechanism of endoplasmic reticulum retention for the alpha,beta-hydrolase fold protein family. J Biol Chem 281: 9667–9676, 2006.[Abstract/Free Full Text]
67. De Praeter CM, Gerwig GJ, Bause E, Nuytinck LK, Vliegenthart JF, Breuer W, Kamerling JP, Espeel MF, Martin JJ, De Paepe AM, Chan NW, Dacremont GA, Van Coster RN. A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency. Am J Hum Genet 66: 1744–1756, 2000.[CrossRef][Web of Science][Medline]
68. De Silva AM, Balch WE, Helenius A. Quality control in the endoplasmic reticulum: folding and misfolding of vesicular stomatitis virus G protein in cells and in vitro. J Cell Biol 111: 857–866, 1990.[Abstract/Free Full Text]
69. De Virgilio M, Kitzmuller C, Schwaiger E, Klein M, Kreibich G, Ivessa NE. Degradation of a short-lived glycoprotein from the lumen of the endoplasmic reticulum: the role of N-linked glycans and the unfolded protein response. Mol Biol Cell 10: 4059–4073, 1999.[Abstract/Free Full Text]
70. DeLeo FR, Goedken M, McCormick SJ, Nauseef WM. A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. J Clin Invest 101: 2900–2909, 1998.[Web of Science][Medline]
71. Denic V, Quan EM, Weissman JS. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126: 349–359, 2006.[CrossRef][Web of Science][Medline]
72. Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ. Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature 358: 761–764, 1992.[CrossRef][Medline]
73. Denzel A, Molinari M, Trigueros C, Martin JE, Velmurgan S, Brown S, Stamp G, Owen MJ. Early postnatal death and motor disorders in mice congenitally deficient in calnexin expression. Mol Cell Biol 22: 7398–7404, 2002.[Abstract/Free Full Text]
74. Deprez P, Gautschi M, Helenius A. More than one glycan is needed for ER glucosidase II to allow entry of glycoproteins into the calnexin/calreticulin cycle. Mol Cell 19: 183–195, 2005.[CrossRef][Web of Science][Medline]
75. Desilva MG, Notkins AL, Lan MS. Molecular characterization of a pancreas-specific protein disulfide isomerase, PDIp. DNA Cell Biol 16: 269–274, 1997.[Web of Science][Medline]
76. Di Jeso B, Park YN, Ulianich L, Treglia AS, Urbanas ML, High S, Arvan P. Mixed-disulfide folding intermediates between thyroglobulin and endoplasmic reticulum resident oxidoreductases ERp57 and protein disulfide isomerase. Mol Cell Biol 25: 9793–9805, 2005.[Abstract/Free Full Text]
77. Dollins DE, Immormino RM, Gewirth DT. Structure of unliganded GRP94, the endoplasmic reticulum Hsp90. Basis for nucleotide-induced conformational change. J Biol Chem 280: 30438–30447, 2005.[Abstract/Free Full Text]
78. Drenth JP, Martina JA, Te Morsche RH, Jansen JB, Bonifacino JS. Molecular characterization of hepatocystin, the protein that is defective in autosomal dominant polycystic liver disease. Gastroenterology 126: 1819–1827, 2004.[CrossRef][Web of Science][Medline]
79. Drenth JP, Martina JA, van de Kerkhof R, Bonifacino JS, Jansen JB. Polycystic liver disease is a disorder of cotranslational protein processing. Trends Mol Med 11: 37–42, 2005.[CrossRef][Web of Science][Medline]
80. Driessen AJ. Cell biology: two pores better than one? Nature 438: 299–300, 2005.[CrossRef][Medline]
81. Druhan LJ, Ai J, Massullo P, Kindwall-Keller T, Ranalli MA, Avalos BR. Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia. Blood 105: 584–591, 2005.[Abstract/Free Full Text]
82. Dulis BH, Kloppel TM, Grey HM, Kubo RT. Regulation of catabolism of IgM heavy chains in a B lymphoma cell line. J Biol Chem 257: 4369–4374, 1982.[Abstract/Free Full Text]
83. Ellgaard L, Molinari M, Helenius A. Setting the standards: quality control in the secretory pathway. Science 286: 1882–1888, 1999.[Abstract/Free Full Text]
84. Ellgaard L, Ruddock LW. The human protein disulfide isomerase family: substrate interactions and functional properties. EMBO Rep 6: 28–32, 2005.[CrossRef][Web of Science][Medline]
85. Ellis J. Proteins as molecular chaperones. Nature 328: 378–379, 1987.[CrossRef][Medline]
86. Eriksson KK, Vago R, Calanca V, Galli C, Paganetti P, Molinari M. EDEM contributes to maintenance of protein folding efficiency and secretory capacity. J Biol Chem 279: 44600–44605, 2004.[Abstract/Free Full Text]
87. Ermonval M, Kitzmuller C, Mir AM, Cacan R, Ivessa NE. N-glycan structure of a short-lived variant of ribophorin I expressed in the MadIA214 glycosylation-defective cell line reveals the role of a mannosidase that is not ER mannosidase I in the process of glycoprotein degradation. Glycobiology 11: 565–576, 2001.[Abstract/Free Full Text]
88. Eschrich S, Yang I, Bloom G, Kwong KY, Boulware D, Cantor A, Coppola D, Kruhoffer M, Aaltonen L, Orntoft TF, Quackenbush J, Yeatman TJ. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 23: 3526–3535, 2005.[Abstract/Free Full Text]
89. Everett LA, Green ED. A family of mammalian anion transporters and their involvement in human genetic diseases. Hum Mol Genet 8: 1883–1891, 1999.[Abstract/Free Full Text]
90. Fan JQ, Ishii S, Asano N, Suzuki Y. Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med 5: 112–115, 1999.[CrossRef][Web of Science][Medline]
91. Fanchiotti S, Fernandez F, D'Alessio C, Parodi AJ. The UDP-Glc:glycoprotein glucosyltransferase is essential for Schizosaccharomyces pombe viability under conditions of extreme endoplasmic reticulum stress. J Cell Biol 143: 625–635, 1998.[Abstract/Free Full Text]
92. Fernandez FS, Trombetta SE, Hellman U, Parodi AJ. Purification to homogeneity of UDP-glucose:glycoprotein glucosyltransferase from Schizosaccharomyces pombe and apparent absence of the enzyme from Saccharomyces cerevisiae. J Biol Chem 269: 30701–30706, 1994.[Abstract/Free Full Text]
93. Ficker E, Obejero-Paz CA, Zhao S, Brown AM. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem 277: 4989–4998, 2002.[Abstract/Free Full Text]
94. Fiebiger E, Story C, Ploegh HL, Tortorella D. Visualization of the ER-to-cytosol dislocation reaction of a type I membrane protein. EMBO J 21: 1041–1053, 2002.[CrossRef][Web of Science][Medline]
95. Fischer G, Bang H, Mech C. Determination of enzymatic catalysis for the cis-trans-isomerization of peptide binding in proline-containing peptides. Biomed Biochim Acta 43: 1101–1111, 1984.[Web of Science][Medline]
96. Fischer G, Wittmann-Liebold B, Lang K, Kiefhaber T, Schmid FX. Cyclophilin and peptidyl-prolyl cis-trans isomerase are probably identical proteins. Nature 337: 476–478, 1989.[CrossRef][Medline]
97. Fliegel L, Burns K, MacLennan DH, Reithmeier RA, Michalak M. Molecular cloning of the high affinity calcium-binding protein (calreticulin) of skeletal muscle sarcoplasmic reticulum. J Biol Chem 264: 21522–21528, 1989.[Abstract/Free Full Text]
98. Forsayeth JR, Gu Y, Hall ZW. BiP forms stable complexes with unassembled subunits of the acetylcholine receptor in transfected COS cells and in C2 muscle cells. J Cell Biol 117: 841–847, 1992.[Abstract/Free Full Text]
99. Foulquier F, Duvet S, Klein A, Mir AM, Chirat F, Cacan R. Endoplasmic reticulum-associated degradation of glycoproteins bearing Man5GlcNAc2 and Man9GlcNAc2 species in the MI8–5 CHO cell line. Eur J Biochem 271: 398–404, 2004.[Web of Science][Medline]
100. Foulquier F, Harduin-Lepers A, Duvet S, Marchal I, Mir AM, Delannoy P, Chirat F, Cacan R. The unfolded protein response in a dolichyl phosphate mannose-deficient Chinese hamster ovary cell line points out the key role of a demannosylation step in the quality-control mechanism of N-glycoproteins. Biochem J 362: 491–498, 2002.[CrossRef][Web of Science][Medline]
101. Frenkel Z, Gregory W, Kornfeld S, Lederkremer GZ. Endoplasmic reticulum-associated degradation of mammalian glycoproteins involves sugar chain trimming to Man6–5GlcNAc2. J Biol Chem 278: 34119–34124, 2003.[Abstract/Free Full Text]
102. Frickel EM, Frei P, Bouvier M, Stafford WF, Helenius A, Glockshuber R, Ellgaard L. ERp57 is a multifunctional thiol-disulfide oxidoreductase. J Biol Chem 279: 18277–18287, 2004.[Abstract/Free Full Text]
103. Frickel EM, Riek R, Jelesarov I, Helenius A, Wuthrich K, Ellgaard L. TROSY-NMR reveals interaction between ERp57 and the tip of the calreticulin P-domain. Proc Natl Acad Sci USA 99: 1954–1959, 2002.[Abstract/Free Full Text]
104. Fujita K, Omura S, Silver J. Rapid degradation of CD4 in cells expressing human immunodeficiency virus type 1 Env and Vpu is blocked by proteasome inhibitors. J Gen Virol 78: 619–625, 1997.[Abstract]
105. Furman MH, Loureiro J, Ploegh HL, Tortorella D. Ubiquitinylation of the cytosolic domain of a type I membrane protein is not required to initiate its dislocation from the endoplasmic reticulum. J Biol Chem 278: 34804–34811, 2003.[Abstract/Free Full Text]
106. Ganoza MC, Williams CA. In vitro synthesis of different categories of specific protein by membrane-bound and free ribosomes. Proc Natl Acad Sci USA 63: 1370–1376, 1969.[Abstract/Free Full Text]
107. Gao B, Adhikari R, Howarth M, Nakamura K, Gold MC, Hill AB, Knee R, Michalak M, Elliott T. Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin. Immunity 16: 99–109, 2002.[CrossRef][Web of Science][Medline]
108. Garbi N, Tanaka S, Momburg F, Hammerling GJ. Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57. Nat Immunol 7: 93–102, 2006.[CrossRef][Web of Science][Medline]
109. Gauss R, Jarosch E, Sommer T, Hirsch C. A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat Cell Biol 8: 849–854, 2006.[CrossRef][Web of Science][Medline]
110. Gedeon AK, Colley A, Jamieson R, Thompson EM, Rogers J, Sillence D, Tiller GE, Mulley JC, Gecz J. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nat Genet 22: 400–404, 1999.[CrossRef][Web of Science][Medline]
111. Geier E, Pfeifer G, Wilm M, Lucchiari-Hartz M, Baumeister W, Eichmann K, Niedermann G. A giant protease with potential to substitute for some functions of the proteasome. Science 283: 978–981, 1999.[Abstract/Free Full Text]
112. Gensure RC, Makitie O, Barclay C, Chan C, Depalma SR, Bastepe M, Abuzahra H, Couper R, Mundlos S, Sillence D, Ala Kokko L, Seidman JG, Cole WG, Juppner H. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest 115: 1250–1257, 2005.[CrossRef][Web of Science][Medline]
113. Gething MJ, McCammon K, Sambrook J. Expression of wild-type and mutant forms of influenza hemagglutinin: the role of folding in intracellular transport. Cell 46: 939–950, 1986.[CrossRef][Web of Science][Medline]
114. Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311: 1471–1474, 2006.[Abstract/Free Full Text]
115. Gil G, Faust JR, Chin DJ, Goldstein JL, Brown MS. Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell 41: 249–258, 1985.[CrossRef][Web of Science][Medline]
116. Gilmore R, Walter P, Blobel G. Protein translocation across the endoplasmic reticulum. II. Isolation and characterization of the signal recognition particle receptor. J Cell Biol 95: 470–477, 1982.[Abstract/Free Full Text]
117. Glas R, Bogyo M, McMaster JS, Gaczynska M, Ploegh HL. A proteolytic system that compensates for loss of proteasome function. Nature 392: 618–622, 1998.[CrossRef][Medline]
118. Goldberger RF, Epstein CJ, Anfinsen CB. Acceleration of reactivation of reduced bovine pancreatic ribonuclease by a microsomal system from rat liver. J Biol Chem 238: 628–635, 1963.[Free Full Text]
119. Gong Q, Keeney DR, Molinari M, Zhou Z. Degradation of trafficking-defective long QT syndrome type II mutant channels by the ubiquitin-proteasome pathway. J Biol Chem 280: 19419–19425, 2005.[Abstract/Free Full Text]
120. Gorlich D, Rapoport TA. Protein translocation into proteoliposomes reconstituted from purified components of the endoplasmic reticulum membrane. Cell 75: 615–630, 1993.[CrossRef][Web of Science][Medline]
121. Gothel SF, Marahiel MA. Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci 55: 423–436, 1999.[CrossRef][Web of Science][Medline]
122. Gow A, Lazzarini RA. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nat Genet 13: 422–428, 1996.[CrossRef][Web of Science][Medline]
123. Green M, Graves PN, Zehavi-Willner T, McInnes J, Pestka S. Cell-free translation of immunoglobulin messenger RNA from MOPC-315 plasmacytoma and MOPC-315 NR, a variant synthesizing only light chain. Proc Natl Acad Sci USA 72: 224–228, 1975.[Abstract/Free Full Text]
124. Groothuis T, Neefjes J. The ins and outs of intracellular peptides and antigen presentation by MHC class I molecules. Curr Top Microbiol Immunol 300: 127–148, 2005.[Web of Science][Medline]
125. Gross CN, Irrinki A, Feder JN, Enns CA. Co-trafficking of HFE, a nonclassical major histocompatibility complex class I protein, with the transferrin receptor implies a role in intracellular iron regulation. J Biol Chem 273: 22068–22074, 1998.[Abstract/Free Full Text]
126. Guerin M, Parodi AJ. The UDP-glucose:glycoprotein glucosyltransferase is organized in at least two tightly bound domains from yeast to mammals. J Biol Chem 278: 20540–20546, 2003.[Abstract/Free Full Text]
127. Gurkan C, Stagg SM, Lapointe P, Balch WE. The COPII cage: unifying principles of vesicle coat assembly. Nat Rev Mol Cell Biol 7: 727–738, 2006.[CrossRef][Web of Science][Medline]
128. Haas IG, Wabl M. Immunoglobulin heavy chain binding protein. Nature 306: 387–389, 1983.[CrossRef][Medline]
129. Halaban R, Cheng E, Zhang Y, Moellmann G, Hanlon D, Michalak M, Setaluri V, Hebert DN. Aberrant retention of tyrosinase in the endoplasmic reticulum mediates accelerated degradation of the enzyme and contributes to the dedifferentiated phenotype of amelanotic melanoma cells. Proc Natl Acad Sci USA 94: 6210–6215, 1997.[Abstract/Free Full Text]
130. Hamman BD, Chen JC, Johnson EE, Johnson AE. The aqueous pore through the translocon has a diameter of 40–60 A during cotranslational protein translocation at the ER membrane. Cell 89: 535–544, 1997.[CrossRef][Web of Science][Medline]
131. Hamman BD, Hendershot LM, Johnson AE. BiP maintains the permeability barrier of the ER membrane by sealing the lumenal end of the translocon pore before and early in translocation. Cell 92: 747–758, 1998.[CrossRef][Web of Science][Medline]
132. Hammond C, Braakman I, Helenius A. Role of N-linked oligosaccharide recognition, glucose trimming, calnexin in glycoprotein folding and quality control. Proc Natl Acad Sci USA 91: 913–917, 1994.[Abstract/Free Full Text]
133. Hammond C, Helenius A. Folding of VSV G protein: sequential interaction with BiP and calnexin. Science 266: 456–458, 1994.[Abstract/Free Full Text]
134. Hanks S, Adams S, Douglas J, Arbour L, Atherton DJ, Balci S, Bode H, Campbell ME, Feingold M, Keser G, Kleijer W, Mancini G, McGrath JA, Muntoni F, Nanda A, Teare MD, Warman M, Pope FM, Superti-Furga A, Futreal PA, Rahman N. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet 73: 791–800, 2003.[CrossRef][Web of Science][Medline]
135. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885–889, 2006.[CrossRef][Medline]
136. Hartl FU. Molecular chaperones in cellular protein folding. Nature 381: 571–579, 1996.[CrossRef][Medline]
137. Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295: 1852–1858, 2002.[Abstract/Free Full Text]
138. Hassink GC, Barel MT, van Voorden SB, Kikkert M, Wiertz EJ. Ubiquitination of MHC class I heavy chains is essential for dislocation by human cytomegalovirus-encoded US2 but not US11. J Biol Chem: 30063–30071, 2006.
139. Hebert DN, Foellmer B, Helenius A. Calnexin and calreticulin promote folding, delay oligomerization and suppress degradation of influenza hemagglutinin in microsomes. EMBO J 15: 2961–2968, 1996.[Web of Science][Medline]
140. Hebert DN, Foellmer B, Helenius A. Glucose trimming and reglucosylation determine glycoprotein association with calnexin in the endoplasmic reticulum. Cell 81: 425–433, 1995.[CrossRef][Web of Science][Medline]
141. Hebert DN, Garman SC, Molinari M. The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags. Trends Cell Biol 15: 364–370, 2005.[CrossRef][Web of Science][Medline]
142. Hebert DN, Zhang JX, Chen W, Foellmer B, Helenius A. The number and location of glycans on influenza hemagglutinin determine folding and association with calnexin and calreticulin. J Cell Biol 139: 613–623, 1997.[Abstract/Free Full Text]
143. Hegde RS, Bernstein HD. The surprising complexity of signal sequences. Trends Biochem Sci 31: 563–571, 2006.[CrossRef][Web of Science][Medline]
144. Helenius A. How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum. Mol Biol Cell 5: 253–265, 1994.[Web of Science][Medline]
145. Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 73: 1019–1049, 2004.[CrossRef][Web of Science][Medline]
146. Hendershot LM. The ER function BiP is a master regulator of ER function. Mt Sinai J Med 71: 289–297, 2004.[Medline]
147. Henrissat B, Davies G. Structural and sequence-based classification of glycoside hydrolases. Curr Opin Struct Biol 7: 637–644, 1997.[CrossRef][Web of Science][Medline]
148. Herscovics A. Structure and function of class I alpha 1,2-mannosidases involved in glycoprotein synthesis and endoplasmic reticulum quality control. Biochimie 83: 757–762, 2001.[Medline]
149. Herscovics A, Romero PA, Tremblay LO. The specificity of the yeast and human class I ER alpha 1,2-mannosidases involved in ER quality control is not as strict previously reported. Glycobiology 12: 14G–15G, 2002.[Web of Science][Medline]
150. Hershko A, Ciechanover A, Varshavsky A. Basic Medical Research Award. The ubiquitin system. Nat Med 6: 1073–1081, 2000.[CrossRef][Web of Science][Medline]
151. Hicks SJ, Drysdale JW, Munro HN. Preferential synthesis of ferritin and albumin by different populations of liver polysomes. Science 164: 584–585, 1969.[Abstract/Free Full Text]
152. Higo T, Hattori M, Nakamura T, Natsume T, Michikawa T, Mikoshiba K. Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44. Cell 120: 85–98, 2005.[CrossRef][Web of Science][Medline]
153. Hiller MM, Finger A, Schweiger M, Wolf DH. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273: 1725–1728, 1996.[Abstract/Free Full Text]
154. Hirano N, Shibasaki F, Sakai R, Tanaka T, Nishida J, Yazaki Y, Takenawa T, Hirai H. Molecular cloning of the human glucose-regulated protein ERp57/GRP58, a thiol-dependent reductase. Identification of its secretory form and inducible expression by the oncogenic transformation. Eur J Biochem 234: 336–342, 1995.[Web of Science][Medline]
155. Hirao K, Natsuka Y, Tamura T, Wada I, Morito D, Natsuka S, Romero P, Sleno B, Tremblay LO, Herscovics A, Nagata K, Hosokawa N. EDEM3, a soluble EDEM homolog, enhances glycoprotein ERAD and mannose trimming. J Biol Chem 281: 9650–9658, 2006.[Abstract/Free Full Text]
156. Hirsch C, Blom D, Ploegh HL. A role for N-glycanase in the cytosolic turnover of glycoproteins. EMBO J 22: 1036–1046, 2003.[CrossRef][Web of Science][Medline]
157. Hitt R, Wolf DH. DER7, encoding alpha-glucosidase I is essential for degradation of malfolded glycoproteins of the endoplasmic reticulum. FEMS Yeast Res 4: 815–820, 2004.[CrossRef][Web of Science][Medline]
158. Hosoda A, Kimata Y, Tsuru A, Kohno K. JPDI, a novel endoplasmic reticulum-resident protein containing both a BiP-interacting J-domain and thioredoxin-like motifs. J Biol Chem 278: 2669–2676, 2003.[Abstract/Free Full Text]
159. Hosokawa N, Tremblay LO, You Z, Herscovics A, Wada I, Nagata K. Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I. J Biol Chem 278: 26287–26294, 2003.[Abstract/Free Full Text]
160. Hosokawa N, Wada I, Hasegawa K, Yorihuzi T, Tremblay LO, Herscovics A, Nagata K. A novel ER -mannosidase-like protein accelerates ER-associated degradation. EMBO Rep 2: 415–422, 2001.[Web of Science][Medline]
161. Hosokawa N, Wada I, Natsuka Y, Nagata K. EDEM accelerates ERAD by preventing aberrant dimer formation of misfolded alpha1-antitrypsin. Genes Cells 11: 465–476, 2006.[Abstract/Free Full Text]
162. Hurtley SM, Bole DG, Hoover-Litty H, Helenius A, Copeland CS. Interactions of misfolded influenza virus hemagglutinin with binding protein (BiP). J Cell Biol 108: 2117–2126, 1989.[Abstract/Free Full Text]
163. Hurtley SM, Helenius A. Protein oligomerization in the endoplasmic reticulum. Annu Rev Cell Biol 5: 277–307, 1989.[CrossRef][Web of Science][Medline]
164. Huyer G, Longsworth GL, Mason DL, Mallampalli MP, McCaffery JM, Wright RL, Michaelis S. A striking quality control subcompartment in Saccharomyces cerevisiae: the endoplasmic reticulum-associated compartment. Mol Biol Cell 15: 908–921, 2004.[Abstract/Free Full Text]
165. Huyer G, Piluek WF, Fansler Z, Kreft SG, Hochstrasser M, Brodsky JL, Michaelis S. Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. J Biol Chem 279: 38369–38378, 2004.[Abstract/Free Full Text]
166. Hwang C, Sinskey AJ, Lodish HF. Oxidized redox state of glutathione in the endoplasmic reticulum. Science 257: 1496–1502, 1992.[Abstract/Free Full Text]
167. Ibba M, Soll D. Quality control mechanisms during translation. Science 286: 1893–1897, 1999.[Abstract/Free Full Text]
168. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105: 891–902, 2001.[CrossRef][Web of Science][Medline]
169. Imamura T, Takata Y, Sasaoka T, Takada Y, Morioka H, Haruta T, Sawa T, Iwanishi M, Hu YG, Suzuki Y, Hamada J, Kobayashi M. Two naturally occurring mutations in the kinase domain of insulin receptor accelerate degradation of the insulin receptor and impair the kinase activity. J Biol Chem 269: 31019–31027, 1994.[Abstract/Free Full Text]
170. Immormino RM, Dollins DE, Shaffer PL, Soldano KL, Walker MA, Gewirth DT. Ligand-induced conformational shift in the N-terminal domain of GRP94, an Hsp90 chaperone. J Biol Chem 279: 46162–46171, 2004.[Abstract/Free Full Text]
171. Imperiali B, Rickert KW. Conformational implications of asparagine-linked glycosylation. Proc Natl Acad Sci USA 92: 97–101, 1995.[Abstract/Free Full Text]
172. Ismail N, Ng DT. Have you HRD? Understanding ERAD Is DOAble! Cell 126: 237–239, 2006.[CrossRef][Web of Science][Medline]
173. Ito M, Jameson JL, Ito M. Molecular basis of autosomal dominant neurohypophyseal diabetes insipidus. Cellular toxicity caused by the accumulation of mutant vasopressin precursors within the endoplasmic reticulum. J Clin Invest 99: 1897–1905, 1997.[Web of Science][Medline]
174. Jakob CA, Burda P, Roth J, Aebi M. Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J Cell Biol 142: 1223–1233, 1998.[Abstract/Free Full Text]
175. Jakob CA, Burda P, te Heesen S, Aebi M, Roth J. Genetic tailoring of N-linked oligosaccharides: the role of glucose residues in glycoprotein processing of Saccharomyces cerevisiae in vivo. Glycobiology 8: 155–164, 1998.[Abstract/Free Full Text]
176. Jakubowski H, Goldman E. Editing of errors in selection of amino acids for protein synthesis. Microbiol Rev 56: 412–429, 1992.[Abstract/Free Full Text]
177. Janovick JA, Goulet M, Bush E, Greer J, Wettlaufer DG, Conn PM. Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor. J Pharmacol Exp Ther 305: 608–614, 2003.[Abstract/Free Full Text]
178. Jansens A, van Duijn E, Braakman I. Coordinated nonvectorial folding in a newly synthesized multidomain protein. Science 298: 2401–2403, 2002.[Abstract/Free Full Text]
179. Jarosch E, Geiss-Friedlander R, Meusser B, Walter J, Sommer T. Protein dislocation from the endoplasmic reticulum–pulling out the suspect. Traffic 3: 530–536, 2002.[CrossRef][Web of Science][Medline]
180. Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83: 129–135, 1995.[CrossRef][Web of Science][Medline]
181. Jentsch S, Rumpf S. Cdc48 (p97): a "molecular gearbox" in the ubiquitin pathway? Trends Biochem Sci 32: 6–11, 2007.[CrossRef][Web of Science][Medline]
182. Jessop CE, Chakravarthi S, Garbi N, Hammerling GJ, Lovell S, Bulleid NJ. ERp57 is essential for efficient folding of glycoproteins sharing common structural domains. EMBO J 26: 28–40, 2007.[CrossRef][Web of Science][Medline]
183. Jung V, Kindich R, Kamradt J, Jung M, Muller M, Schulz WA, Engers R, Unteregger G, Stockle M, Zimmermann R, Wullich B. Genomic and expression analysis of the 3q25-q26 amplification unit reveals TLOC1/SEC62 as a probable target gene in prostate cancer. Mol Cancer Res 4: 169–176, 2006.[Abstract/Free Full Text]
184. Kabani M, Kelley SS, Morrow MW, Montgomery DL, Sivendran R, Rose MD, Gierasch LM, Brodsky JL. Dependence of endoplasmic reticulum-associated degradation on the peptide binding domain and concentration of BiP. Mol Biol Cell 14: 3437–3448, 2003.[Abstract/Free Full Text]
185. Kadler KE, Holmes DF, Trotter JA, Chapman JA. Collagen fibril formation. Biochem J 316: 1–11, 1996.[Web of Science][Medline]
186. Kamimoto T, Shoji S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter DH, Yoshimori T. Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem 281: 4467–4476, 2006.[Abstract/Free Full Text]
187. Kang SW, Rane NS, Kim SJ, Garrison JL, Taunton J, Hegde RS. Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway. Cell 127: 999–1013, 2006.[CrossRef][Web of Science][Medline]
188. Kapoor M, Srinivas H, Kandiah E, Gemma E, Ellgaard L, Oscarson S, Helenius A, Surolia A. Interactions of substrate with calreticulin, an endoplasmic reticulum chaperone. J Biol Chem 278: 6194–6200, 2003.[Abstract/Free Full Text]
189. Karaveg K, Moremen KW. Energetics of substrate binding and catalysis by class 1 (glycosylhydrolase family 47) alpha-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J Biol Chem 280: 29837–29848, 2005.[Abstract/Free Full Text]
190. Karaveg K, Siriwardena A, Tempel W, Liu ZJ, Glushka J, Wang BC, Moremen KW. Mechanism of class 1 (glycosylhydrolase family 47) -mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J Biol Chem 280: 16197–16207, 2005.[Abstract/Free Full Text]
191. Kearse KP, Williams DB, Singer A. Persistence of glucose residues on core oligosaccharides prevents association of TCR alpha and TCR beta proteins with calnexin and results specifically in accelerated degradation of nascent TCR alpha proteins within the endoplasmic reticulum. EMBO J 13: 3678–3686, 1994.[Web of Science][Medline]
192. Keller SH, Lindstrom J, Taylor P. Inhibition of glucose trimming with castanospermine reduces calnexin association and promotes proteasome degradation of the alpha-subunit of the nicotinic acetylcholine receptor. J Biol Chem 273: 17064–17072, 1998.[Abstract/Free Full Text]
193. Keller SH, Platoshyn O, Yuan JX. Long QT syndrome-associated I593R mutation in HERG potassium channel activates ER stress pathways. Cell Biochem Biophys 43: 365–377, 2005.[CrossRef][Web of Science][Medline]
194. Kiefhaber T, Quaas R, Hahn U, Schmid FX. Folding of ribonuclease T1.2 Kinetic models for the folding and unfolding reactions. Biochemistry 29: 3061–3070, 1990.[CrossRef][Medline]
195. Kim BE, Smith K, Meagher CK, Petris MJ. A conditional mutation affecting localization of the Menkes disease copper ATPase. Suppression by copper supplementation. J Biol Chem 277: 44079–44084, 2002.[Abstract/Free Full Text]
196. Kim SK, Kim YK, Lee AS. Expression of the glucose-regulated proteins (GRP94 and GRP78) in differentiated and undifferentiated mouse embryonic cells and the use of the GRP78 promoter as an expression system in embryonic cells. Differentiation 42: 153–159, 1990.[Web of Science][Medline]
197. Kincaid MM, Cooper AA. Misfolded proteins traffic from the endoplasmic reticulum (ER) due to ER export signals. Mol Biol Cell 18: 455–463, 2007.[Abstract/Free Full Text]
198. Kitzmuller C, Caprini A, Moore SE, Frenoy JP, Schwaiger E, Kellermann O, Ivessa NE, Ermonval M. Processing of N-linked glycans during endoplasmic-reticulum-associated degradation of a short-lived variant of ribophorin I. Biochem J 376: 687–696, 2003.[CrossRef][Web of Science][Medline]
199. Kjaer S, Ibanez CF. Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET. Hum Mol Genet 12: 2133–2144, 2003.[Abstract/Free Full Text]
200. Klausner RD, Sitia R. Protein degradation in the endoplasmic reticulum. Cell 62: 611–614, 1990.[CrossRef][Web of Science][Medline]
201. Kleizen B, van Vlijmen T, de Jonge HR, Braakman I. Folding of CFTR is predominantly cotranslational. Mol Cell 20: 277–287, 2005.[CrossRef][Web of Science][Medline]
202. Klionsky DJ. The molecular machinery of autophagy: unanswered questions. J Cell Sci 118: 7–18, 2005.[Abstract/Free Full Text]
203. Knittler MR, Dirks S, Haas IG. Molecular chaperones involved in protein degradation in the endoplasmic reticulum: quantitative interaction of the heat shock cognate protein BiP with partially folded immunoglobulin light chains that are degraded in the endoplasmic reticulum. Proc Natl Acad Sci USA 92: 1764–1768, 1995.[Abstract/Free Full Text]
204. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, Kominami E, Tanaka K, Chiba T. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169: 425–434, 2005.[Abstract/Free Full Text]
205. Kopito RR. Biosynthesis and degradation of CFTR. Physiol Rev 79 Suppl: S167–S173, 1999.[Medline]
206. Kopito RR. ER quality control: the cytoplasmic connection. Cell 88: 427–430, 1997.[CrossRef][Web of Science][Medline]
207. Kostova Z, Wolf DH. For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J 22: 2309–2317, 2003.[CrossRef][Web of Science][Medline]
208. Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S. Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4: 191–197, 2002.[CrossRef][Web of Science][Medline]
209. Kowarik M, Kung S, Martoglio B, Helenius A. Protein folding during cotranslational translocation in the endoplasmic reticulum. Mol Cell 10: 769–778, 2002.[CrossRef][Web of Science][Medline]
210. Kozlov G, Maattanen P, Schrag JD, Pollock S, Cygler M, Nagar B, Thomas DY, Gehring K. Crystal structure of the bb' domains of the protein disulfide isomerase ERp57. Structure 14: 1331–1339, 2006.[Medline]
211. Kruse KB, Brodsky JL, McCracken AA. Characterization of an ERAD gene as VPS30/ATG6 reveals two alternative and functionally distinct protein quality control pathways: one for soluble Z variant of human alpha-1 proteinase inhibitor (A1PiZ) and another for aggregates of A1PiZ. Mol Biol Cell 17: 203–212, 2006.[Abstract/Free Full Text]
212. Kruse KB, Dear A, Kaltenbrun ER, Crum BE, George PM, Brennan SO, McCracken AA. Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol 168: 1299–1308, 2006.[Abstract/Free Full Text]
213. Kubota K, Niinuma Y, Kaneko M, Okuma Y, Sugai M, Omura T, Uesugi M, Uehara T, Hosoi T, Nomura Y. Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress. J Neurochem 97: 1259–1268, 2006.[CrossRef][Web of Science][Medline]
214. Kustedjo K, Bracey MH, Cravatt BF. Torsin A and its torsion dystonia-associated mutant forms are lumenal glycoproteins that exhibit distinct subcellular localizations. J Biol Chem 275: 27933–27939, 2000.[Abstract/Free Full Text]
215. Lamande SR, Chessler SD, Golub SB, Byers PH, Chan D, Cole WG, Sillence DO, Bateman JF. Endoplasmic reticulum-mediated quality control of type I collagen production by cells from osteogenesis imperfecta patients with mutations in the pro alpha 1 (I) chain carboxyl-terminal propeptide which impair subunit assembly. J Biol Chem 270: 8642–8649, 1995.[Abstract/Free Full Text]
216. Lau MM, Neufeld EF. A frameshift mutation in a patient with Tay-Sachs disease causes premature termination and defective intracellular transport of the alpha-subunit of beta-hexosaminidase. J Biol Chem 264: 21376–21380, 1989.[Abstract/Free Full Text]
217. Lau PP, Villanueva H, Kobayashi K, Nakamuta M, Chang BH, Chan L. A DnaJ protein, apobec-1-binding protein-2, modulates apolipoprotein B mRNA editing. J Biol Chem 276: 46445–46452, 2001.[Abstract/Free Full Text]
218. Leach MR, Cohen-Doyle MF, Thomas DY, Williams DB. Localization of the lectin, ERp57 binding, polypeptide binding sites of calnexin and calreticulin. J Biol Chem 277: 29686–29697, 2002.[Abstract/Free Full Text]
219. Lederkremer GZ, Glickman MH. A window of opportunity: timing protein degradation by trimming of sugars and ubiquitins. Trends Biochem Sci 30: 297–303, 2005.[CrossRef][Web of Science][Medline]
220. Lee AS. The glucose-regulated proteins: stress induction and clinical applications. Trends Biochem Sci 26: 504–510, 2001.[CrossRef][Web of Science][Medline]
221. Lee JW, Beebe K, Nangle LA, Jang J, Longo-Guess CM, Cook SA, Davisson MT, Sundberg JP, Schimmel P, Ackerman SL. Editing-defective tRNA synthase causes protein misfolding and neurodegeneration. Nature 443: 50–55, 2006.[CrossRef][Medline]
222. Lee RJ, Liu CW, Harty C, McCracken AA, Latterich M, Romisch K, DeMartino GN, Thomas PJ, Brodsky JL. Uncoupling retro-translocation and degradation in the ER-associated degradation of a soluble protein. EMBO J 23: 2206–2215, 2004.[CrossRef][Web of Science][Medline]
223. Levinthal C. Are there pathways for protein folding? J Chim Phys 65: 44–45, 1968.
224. Li Y, Lu W, Schwartz AL, Bu G. Receptor-associated protein facilitates proper folding and maturation of the low-density lipoprotein receptor and its class 2 mutants. Biochemistry 41: 4921–4928, 2002.[CrossRef][Medline]
225. Li Y, Luo L, Thomas DY, Kang CY. The HIV-1 Env protein signal sequence retards its cleavage and down-regulates the glycoprotein folding. Virology 272: 417–428, 2000.[CrossRef][Web of Science][Medline]
226. Li Z, Srivastava PK. Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation. EMBO J 12: 3143–3151, 1993.[Web of Science][Medline]
227. Lievremont JP, Rizzuto R, Hendershot L, Meldolesi J. BiP, a major chaperone protein of the endoplasmic reticulum lumen, plays a direct and important role in the storage of the rapidly exchanging pool of Ca²⁺. J Biol Chem 272: 30873–30879, 1997.[Abstract/Free Full Text]
228. Lilley BN, Ploegh HL. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429: 834–840, 2004.[CrossRef][Medline]
229. Lilley BN, Ploegh HL. Multiprotein complexes that link dislocation, ubiquitination, extraction of misfolded proteins from the endoplasmic reticulum membrane. Proc Natl Acad Sci USA 102: 14296–14301, 2005.[Abstract/Free Full Text]
230. Liu Y, Choudhury P, Cabral CM, Sifers RN. Intracellular disposal of incompletely folded human alpha1-antitrypsin involves release from calnexin and post-translational trimming of asparagine-linked oligosaccharides. J Biol Chem 272: 7946–7951, 1997.[Abstract/Free Full Text]
231. Loftfield RB, Vanderjagt D. The frequency of errors in protein biosynthesis. Biochem J 128: 1353–1356, 1972.[Web of Science][Medline]
232. Loo TW, Bartlett MC, Clarke DM. Rescue of folding defects in ABC transporters using pharmacological chaperones. J Bioenerg Biomembr 37: 501–507, 2005.[CrossRef][Web of Science][Medline]
233. Lord JM, Roberts LM, Lencer WI. Entry of protein toxins into mammalian cells by crossing the endoplasmic reticulum membrane: co-opting basic mechanisms of endoplasmic reticulum-associated degradation. Curr Top Microbiol Immunol 300: 149–168, 2005.[Web of Science][Medline]
234. Loureiro J, Lilley BN, Spooner E, Noriega V, Tortorella D, Ploegh HL. Signal peptide peptidase is required for dislocation from the endoplasmic reticulum. Nature 441: 894–897, 2006.[CrossRef][Medline]
235. Luo S, Mao C, Lee B, Lee AS. GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol Cell Biol 26: 5688–5697, 2006.[Abstract/Free Full Text]
236. Lyons SE, Bruck ME, Bowie EJ, Ginsburg D. Impaired intracellular transport produced by a subset of type IIA von Willebrand disease mutations. J Biol Chem 267: 4424–4430, 1992.[Abstract/Free Full Text]
237. Maattanen P, Kozlov G, Gehring K, Thomas DY. ERp57 and PDI: multifunctional protein disulfide isomerases with similar domain architectures but differing substrate–partner associations. Biochem Cell Biol 84: 881–889, 2006.[Web of Science][Medline]
238. Mach B, Faust C, Vassalli P. Purification of 14S messenger RNA of immunoglobulin light chain that codes for a possible light-chain precursor. Proc Natl Acad Sci USA 70: 451–455, 1973.[Abstract/Free Full Text]
239. Machamer CE, Doms RW, Bole DG, Helenius A, Rose JK. Heavy chain binding protein recognizes incompletely disulfide-bonded forms of vesicular stomatitis virus G protein. J Biol Chem 265: 6879–6883, 1990.[Abstract/Free Full Text]
240. Magnuson B, Rainey EK, Benjamin T, Baryshev M, Mkrtchian S, Tsai B. ERp29 triggers a conformational change in polyomavirus to stimulate membrane binding. Mol Cell 20: 289–300, 2005.[CrossRef][Web of Science][Medline]
241. Mancini R, Fagioli C, Fra AM, Maggioni C, Sitia R. Degradation of unassembled soluble Ig subunits by cytosolic proteasomes: evidence that retrotranslocation and degradation are coupled events. FASEB J 14: 769–778, 2000.[Abstract/Free Full Text]
242. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev 86: 1133–1149, 2006.[Abstract/Free Full Text]
243. Marquardt T, Helenius A. Misfolding and aggregation of newly synthesized proteins in the endoplasmic reticulum. J Cell Biol 117: 505–513, 1992.[Abstract/Free Full Text]
244. Marr N, Bichet DG, Lonergan M, Arthus MF, Jeck N, Seyberth HW, Rosenthal W, van Os CH, Oksche A, Deen PM. Heteroligomerization of an Aquaporin-2 mutant with wild-type Aquaporin-2 and their misrouting to late endosomes/lysosomes explains dominant nephrogenic diabetes insipidus. Hum Mol Genet 11: 779–789, 2002.[Abstract/Free Full Text]
245. Martoglio B, Dobberstein B. Signal sequences: more than just greasy peptides. Trends Cell Biol 8: 410–415, 1998.[CrossRef][Web of Science][Medline]
246. Mast SW, Diekman K, Karaveg K, Davis A, Sifers RN, Moremen KW. Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology 15: 421–436, 2005.[Abstract/Free Full Text]
247. Matlack KE, Misselwitz B, Plath K, Rapoport TA. BiP acts as a molecular ratchet during posttranslational transport of prepro-alpha factor across the ER membrane. Cell 97: 553–564, 1999.[CrossRef][Web of Science][Medline]
248. Matlack KE, Walter P. The 70 carboxyl-terminal amino acids of nascent secretory proteins are protected from proteolysis by the ribosome and the protein translocation apparatus of the endoplasmic reticulum membrane. J Biol Chem 270: 6170–6180, 1995.[Abstract/Free Full Text]
249. Mayer TU, Braun T, Jentsch S. Role of the proteasome in membrane extraction of a short-lived ER-transmembrane protein. EMBO J 17: 3251–3257, 1998.[CrossRef][Web of Science][Medline]
250. McCracken AA, Brodsky JL. Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, ATP. J Cell Biol 132: 291–298, 1996.[Abstract/Free Full Text]
251. Medeiros-Neto G, Kim PS, Yoo SE, Vono J, Targovnik HM, Camargo R, Hossain SA, Arvan P. Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones. J Clin Invest 98: 2838–2844, 1996.[Web of Science][Medline]
252. Meerovitch K, Wing S, Goltzman D. Preproparathyroid hormone-related protein, a secreted peptide, is a substrate for the ubiquitin proteolytic system. J Biol Chem 272: 6706–6713, 1997.[Abstract/Free Full Text]
253. Melnick J, Dul JL, Argon Y. Sequential interaction of the chaperones BiP and GRP94 with immunoglobulin chains in the endoplasmic reticulum. Nature 370: 373–375, 1994.[CrossRef][Medline]
254. Mesaeli N, Nakamura K, Zvaritch E, Dickie P, Dziak E, Krause KH, Opas M, MacLennan DH, Michalak M. Calreticulin is essential for cardiac development. J Cell Biol 144: 857–868, 1999.[Abstract/Free Full Text]
255. Meunier L, Usherwood YK, Chung KT, Hendershot LM. A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins. Mol Biol Cell 13: 4456–4469, 2002.[Abstract/Free Full Text]
256. Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: the long road to destruction. Nat Cell Biol 7: 766–772, 2005.[CrossRef][Web of Science][Medline]
257. Meyer DI, Dobberstein B. Identification and characterization of a membrane component essential for the translocation of nascent proteins across the membrane of the endoplasmic reticulum. J Cell Biol 87: 503–508, 1980.[Abstract/Free Full Text]
258. Michalak M. Calreticulin. In: Molecular Biology Intelligence Unit. Austin, TX: Landes, 1996.
259. Milstein C, Brownlee GG, Harrison TM, Mathews MB. A possible precursor of immunoglobulin light chains. Nat New Biol 239: 117–120, 1972.[CrossRef][Web of Science][Medline]
260. Misaghi S, Pacold ME, Blom D, Ploegh HL, Korbel GA. Using a small molecule inhibitor of peptide: N-glycanase to probe its role in glycoprotein turnover. Chem Biol 11: 1677–1687, 2004.[CrossRef][Web of Science][Medline]
261. Mitra K, Schaffitzel C, Shaikh T, Tama F, Jenni S, Brooks CL, 3rd Ban N, Frank J. Structure of the E. coli protein-conducting channel bound to a translating ribosome. Nature 438: 318–324, 2005.[CrossRef][Medline]
262. Molinari M, Calanca V, Galli C, Lucca P, Paganetti P. Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299: 1397–1400, 2003.[Abstract/Free Full Text]
263. Molinari M, Eriksson KK, Calanca V, Galli C, Cresswell P, Michalak M, Helenius A. Contrasting functions of calreticulin and calnexin in glycoprotein folding and ER quality control. Mol Cell 13: 125–135, 2004.[CrossRef][Web of Science][Medline]
264. Molinari M, Galli C, Piccaluga V, Pieren M, Paganetti P. Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER. J Cell Biol 158: 247–257, 2002.[Abstract/Free Full Text]
265. Molinari M, Galli C, Vanoni O, Arnold SM, Kaufman RJ. Persistent glycoprotein misfolding activates the glucosidase II/UGT1-driven calnexin cycle to delay aggregation and loss of folding competence. Mol Cell 20: 503–512, 2005.[CrossRef][Web of Science][Medline]
266. Molinari M, Helenius A. Chaperone selection during glycoprotein translocation into the endoplasmic reticulum. Science 288: 331–333, 2000.[Abstract/Free Full Text]
267. Molinari M, Helenius A. Glycoproteins form mixed disulphides with oxidoreductases during folding in living cells. Nature 402: 90–93, 1999.[CrossRef][Medline]
268. Molinari M, Sitia R. The secretory capacity of a cell depends on the efficiency of endoplasmic reticulum-associated degradation. Curr Top Microbiol Immunol 300: 1–15, 2005.[Web of Science][Medline]
268. Molinari M. N-glycan structure dictates extension of protein folding or onset of disposal. Nature Chem Biol 3: 313–320, 2007.[CrossRef]
269. Montecucco C, Molinari M. Microbiology: death of a chaperone. Nature 443: 511–512, 2006.[CrossRef][Medline]
270. Moore SE, Spiro RG. Inhibition of glucose trimming by castanospermine results in rapid degradation of unassembled major histocompatibility complex class I molecules. J Biol Chem 268: 3809–3812, 1993.[Abstract/Free Full Text]
271. Morello JP, Petaja-Repo UE, Bichet DG, Bouvier M. Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci 21: 466–469, 2000.[CrossRef][Medline]
272. Morello JP, Salahpour A, Laperriere A, Bernier V, Arthus MF, Lonergan M, Petaja-Repo U, Angers S, Morin D, Bichet DG, Bouvier M. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants. J Clin Invest 105: 887–895, 2000.[Web of Science][Medline]
273. Moremen KW. Alpha-Mannosidases in Asparagine-Linked Oligosaccharide Processing and Catabolism. New York: Wiley, 2000.
274. Moremen KW, Molinari M. N-linked glycan recognition and processing: the molecular basis of endoplasmic reticulum quality control. Curr Opin Struct Biol: 592–599, 2006.
275. Mueller B, Lilley BN, Ploegh HL. SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J Cell Biol 175: 261–270, 2006.
276. Naef R, Adlkofer K, Lescher B, Suter U. Aberrant protein trafficking in Trembler suggests a disease mechanism for hereditary human peripheral neuropathies. Mol Cell Neurosci 9: 13–25, 1997.[CrossRef][Web of Science][Medline]
277. Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K. Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J Cell Biol 150: 1499–1506, 2000.[Abstract/Free Full Text]
278. Nagata K. Hsp47: a collagen-specific molecular chaperone. Trends Biochem Sci 21: 22–26, 1996.[Medline]
279. Nauseef WM, McCormick SJ, Clark RA. Calreticulin functions as a molecular chaperone in the biosynthesis of myeloperoxidase. J Biol Chem 270: 4741–4747, 1995.[Abstract/Free Full Text]
280. Neufeld EB, Stonik JA, Demosky SJ Jr, Knapper CL, Combs CA, Cooney A, Comly M, Dwyer N, Blanchette-Mackie J, Remaley AT, Santamarina-Fojo S, Brewer HB, Jr. The ABCA1 transporter modulates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease. J Biol Chem 279: 15571–15578, 2004.[Abstract/Free Full Text]
281. Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, Moussalli MJ, Hauri HP, Ciavarella N, Kaufman RJ, Ginsburg D. Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII. Cell 93: 61–70, 1998.[CrossRef][Web of Science][Medline]
282. Nilsson IM, von Heijne G. Determination of the distance between the oligosaccharyltransferase active site and the endoplasmic reticulum membrane. J Biol Chem 268: 5798–5801, 1993.[Abstract/Free Full Text]
283. Nishikawa S, Brodsky JL, Nakatsukasa K. Roles of molecular chaperones in endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD). J Biochem 137: 551–555, 2005.[Abstract/Free Full Text]
284. Nishikawa S, Fewell SW, Kato Y, Brodsky JL, Endo T. Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J Cell Biol 153: 1061–1070, 2001.[Abstract/Free Full Text]
285. Noorwez SM, Kuksa V, Imanishi Y, Zhu L, Filipek S, Palczewski K, Kaushal S. Pharmacological chaperone-mediated in vivo folding and stabilization of the P23H-opsin mutant associated with autosomal dominant retinitis pigmentosa. J Biol Chem 278: 14442–14450, 2003.[Abstract/Free Full Text]
286. Oda Y, Hosokawa N, Wada I, Nagata K. EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299: 1394–1397, 2003.[Abstract/Free Full Text]
287. Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 172: 383–393, 2006.[Abstract/Free Full Text]
288. Ogle JM, Ramakrishnan V. Structural insights into translational fidelity. Annu Rev Biochem 74: 129–177, 2005.[CrossRef][Web of Science][Medline]
289. Okumiya T, Ishii S, Takenaka T, Kase R, Kamei S, Sakuraba H, Suzuki Y. Galactose stabilizes various missense mutants of alpha-galactosidase in Fabry disease. Biochem Biophys Res Commun 214: 1219–1224, 1995.[CrossRef][Web of Science][Medline]
290. Olivari S, Cali T, Salo KE, Paganetti P, Ruddock LW, Molinari M. EDEM1 regulates ER-associated degradation by accelerating de-mannosylation of folding-defective polypeptides and by inhibiting their covalent aggregation. Biochem Biophys Res Commun 349: 1278–1284, 2006.[CrossRef][Web of Science][Medline]
291. Olivari S, Galli C, Alanen H, Ruddock L, Molinari M. A novel stress-induced EDEM variant regulating endoplasmic reticulum-associated glycoprotein degradation. J Biol Chem 280: 2424–2428, 2005.[Abstract/Free Full Text]
291. Olivari S, Molinari M. Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. FEBS Lett 581: 3658–3664, 2007.[CrossRef][Web of Science][Medline]
292. Oliver JD, Hresko RC, Mueckler M, High S. The Glut 1 glucose transporter interacts with calnexin and calreticulin. J Biol Chem 271: 13691–13696, 1996.[Abstract/Free Full Text]
293. Oliver JD, Roderick HL, Llewellyn DH, High S. ERp57 functions as a subunit of specific complexes formed with the ER lectins calreticulin and calnexin. Mol Biol Cell 10: 2573–2582, 1999.[Abstract/Free Full Text]
294. Oliver JD, van der Wal FJ, Bulleid NJ, High S. Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Science 275: 86–88, 1997.[Abstract/Free Full Text]
295. Otteken A, Moss B. Calreticulin interacts with newly synthesized human immunodeficiency virus type 1 envelope glycoprotein, suggesting a chaperone function similar to that of calnexin. J Biol Chem 271: 97–103, 1996.[Abstract/Free Full Text]
296. Ou WJ, Cameron PH, Thomas DY, Bergeron JJ. Association of folding intermediates of glycoproteins with calnexin during protein maturation. Nature 364: 771–776, 1993.[CrossRef][Medline]
297. Oyadomari S, Yun C, Fisher EA, Kreglinger N, Kreibich G, Oyadomari M, Harding HP, Goodman AG, Harant H, Garrison JL, Taunton J, Katze MG, Ron D. Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload. Cell 126: 727–739, 2006.[CrossRef][Web of Science][Medline]
298. Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313: 1137–1140, 2006.[Abstract/Free Full Text]
299. Palade GE. A small particulate component of the cytoplasm. J Biophys Biochem Cytol 1: 59–68, 1955.[Medline]
300. Palmiter RD. Quantitation of parameters that determine the rate of ovalbumin synthesis. Cell 4: 189, 1975.[CrossRef][Web of Science][Medline]
301. Parodi AJ, Behrens NH, Leloir LF, Carminatti H. The role of polyprenol-bound saccharides as intermediates in glycoprotein synthesis in liver. Proc Natl Acad Sci USA 69: 3268–3272, 1972.[Abstract/Free Full Text]
302. Paton AW, Beddoe T, Thorpe CM, Whisstock JC, Wilce MC, Rossjohn J, Talbot UM, Paton JC. AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP. Nature 443: 548–552, 2006.[CrossRef][Medline]
303. Payne AS, Kelly EJ, Gitlin JD. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci USA 95: 10854–10859, 1998.[Abstract/Free Full Text]
304. Perlmutter DH. Alpha-1-antitrypsin deficiency: biochemistry and clinical manifestations. Ann Med 28: 385–394, 1996.[Web of Science][Medline]
305. Peterson JR, Ora A, Van PN, Helenius A. Transient, lectin-like association of calreticulin with folding intermediates of cellular and viral glycoproteins. Mol Biol Cell 6: 1173–1184, 1995.[Abstract]
306. Petrescu AJ, Milac AL, Petrescu SM, Dwek RA, Wormald MR. Statistical analysis of the protein environment of N-glycosylation sites: implications for occupancy, structure, folding. Glycobiology 14: 103–114, 2004.[Abstract/Free Full Text]
307. Pieren M, Galli C, Denzel A, Molinari M. The use of calnexin and calreticulin by cellular and viral glycoproteins. J Biol Chem 280: 28265–28271, 2005.[Abstract/Free Full Text]
308. Pilon M, Schekman R, Romisch K. Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO J 16: 4540–4548, 1997.[CrossRef][Web of Science][Medline]
309. Pipe SW, Morris JA, Shah J, Kaufman RJ. Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin. J Biol Chem 273: 8537–8544, 1998.[Abstract/Free Full Text]
310. Plemper RK, Bohmler S, Bordallo J, Sommer T, Wolf DH. Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 388: 891–895, 1997.[CrossRef][Medline]
310. Ploegh HL. A lipid-based model for the creation of an escape hatch from the ER. Nature 448: 435–438, 2007.[CrossRef][Medline]
311. Pollock S, Kozlov G, Pelletier MF, Trempe JF, Jansen G, Sitnikov D, Bergeron JJ, Gehring K, Ekiel I, Thomas DY. Specific interaction of ERp57 and calnexin determined by NMR spectroscopy and an ER two-hybrid system. EMBO J 23: 1020–1029, 2004.[CrossRef][Web of Science][Medline]
312. Popescu CI, Paduraru C, Dwek RA, Petrescu SM. Soluble tyrosinase is an endoplasmic reticulum (ER)-associated degradation substrate retained in the ER by calreticulin and BiP/GRP78 and not calnexin. J Biol Chem 280: 13833–13840, 2005.[Abstract/Free Full Text]
313. Prols F, Mayer MP, Renner O, Czarnecki PG, Ast M, Gassler C, Wilting J, Kurz H, Christ B. Upregulation of the cochaperone Mdg1 in endothelial cells is induced by stress and during in vitro angiogenesis. Exp Cell Res 269: 42–53, 2001.[CrossRef][Web of Science][Medline]
314. Puig A, Gilbert HF. Anti-chaperone behavior of BiP during the protein disulfide isomerase-catalyzed refolding of reduced denatured lysozyme. J Biol Chem 269: 25889–25896, 1994.[Abstract/Free Full Text]
315. Qu D, Teckman JH, Omura S, Perlmutter DH. Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J Biol Chem 271: 22791–22795, 1996.[Abstract/Free Full Text]
316. Quan H, Fan G, Wang CC. Independence of the chaperone activity of protein disulfide isomerase from its thioredoxin-like active site. J Biol Chem 270: 17078–17080, 1995.[Abstract/Free Full Text]
317. Randow F, Seed B. Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nat Cell Biol 3: 891–896, 2001.[CrossRef][Web of Science][Medline]
318. Redman CM. Biosynthesis of serum proteins and ferritin by free and attached ribosomes of rat liver. J Biol Chem 244: 4308–4315, 1969.[Abstract/Free Full Text]
319. Redman CM, Sabatini DD. Vectorial discharge of peptides released by puromycin from attached ribosomes. Proc Natl Acad Sci USA 56: 608–615, 1966.[Free Full Text]
320. Redman CM, Siekevitz P, Palade GE. Synthesis and transfer of amylase in pigeon pancreatic micromosomes. J Biol Chem 241: 1150–1158, 1966.[Abstract/Free Full Text]
321. Reggiori F, Klionsky DJ. Autophagosomes: biogenesis from scratch? Curr Opin Cell Biol 17: 415–422, 2005.[CrossRef][Web of Science][Medline]
322. Reits E, Neijssen J, Herberts C, Benckhuijsen W, Janssen L, Drijfhout JW, Neefjes J. A major role for TPPII in trimming proteasomal degradation products for MHC class I antigen presentation. Immunity 20: 495–506, 2004.[CrossRef][Web of Science][Medline]
323. Ritter C, Helenius A. Recognition of local glycoprotein misfolding by the ER folding sensor UDP-glucose:glycoprotein glucosyltransferase. Nat Struct Biol 7: 278–280, 2000.[CrossRef][Web of Science][Medline]
324. Ritter C, Quirin K, Kowarik M, Helenius A. Minor folding defects trigger local modification of glycoproteins by the ER folding sensor GT. EMBO J 24: 1730–1738, 2005.[CrossRef][Web of Science][Medline]
325. Rodan AR, Simons JF, Trombetta ES, Helenius A. N-linked oligosaccharides are necessary and sufficient for association of glycosylated forms of bovine RNase with calnexin and calreticulin. EMBO J 15: 6921–6930, 1996.[Web of Science][Medline]
326. Ron I, Horowitz M. ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum Mol Genet 14: 2387–2398, 2005.[Abstract/Free Full Text]
327. Rose JK, Doms RW. Regulation of protein export from the endoplasmic reticulum. Annu Rev Cell Biol 4: 257–288, 1988.[CrossRef][Web of Science][Medline]
328. Rosenberger RF, Hilton J. The frequency of transcriptional and translational errors at nonsense codons in the lacZ gene of Escherichia coli. Mol Gen Genet 191: 207–212, 1983.[CrossRef][Web of Science][Medline]
329. Ross CA, Poirier MA. Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6: 891–898, 2005.[CrossRef][Web of Science][Medline]
330. Rudiger S, Buchberger A, Bukau B. Interaction of Hsp70 chaperones with substrates. Nat Struct Biol 4: 342–349, 1997.[CrossRef][Web of Science][Medline]
331. Sabatini DD, Blobel G. Controlled proteolysis of nascent polypeptides in rat liver cell fractions. II. Location of the polypeptides in rough microsomes. J Cell Biol 45: 146–157, 1970.[Abstract/Free Full Text]
332. Saliba RS, Munro PM, Luthert PJ, Cheetham ME. The cellular fate of mutant rhodopsin: quality control, degradation and aggresome formation. J Cell Sci 115: 2907–2918, 2002.[Abstract/Free Full Text]
333. Sato S, Ward CL, Kopito RR. Cotranslational ubiquitination of cystic fibrosis transmembrane conductance regulator in vitro. J Biol Chem 273: 7189–7192, 1998.[Abstract/Free Full Text]
334. Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW. Chemical chaperones increase the cellular activity of N370S -glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci USA 99: 15428–15433, 2002.[Abstract/Free Full Text]
335. Schechter I. Biologically and chemically pure mRNA coding for a mouse immunoglobulin L-chain prepared with the aid of antibodies and immobilized oligothymidine. Proc Natl Acad Sci USA 70: 2256–2260, 1973.[Abstract/Free Full Text]
336. Schechter I. Partial amino acid sequence of the precursor of immunoglobulin light chain programmed by messenger RNA in vitro. Science 188: 160–162, 1975.[Abstract/Free Full Text]
337. Schild H, Rammensee HG. Perfect use of imperfection. Nature 404: 709–710, 2000.[CrossRef][Medline]
338. Schmeckpeper BJ, Cory S, Adams JM. Translation of immunoglobulin mRNAs in a wheat germ cell-free system. Mol Biol Rep 1: 355–363, 1974.[CrossRef][Web of Science][Medline]
339. Schrag JD, Bergeron JJ, Li Y, Borisova S, Hahn M, Thomas DY, Cygler M. The Structure of calnexin, an ER chaperone involved in quality control of protein folding. Mol Cell 8: 633–644, 2001.[CrossRef][Web of Science][Medline]
340. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem 74: 739–789, 2005.[CrossRef][Web of Science][Medline]
341. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404: 770–774, 2000.[CrossRef][Medline]
342. Sekijima Y, Wiseman RL, Matteson J, Hammarstrom P, Miller SR, Sawkar AR, Balch WE, Kelly JW. The biological and chemical basis for tissue-selective amyloid disease. Cell 121: 73–85, 2005.[CrossRef][Web of Science][Medline]
343. Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach-Faller N, Rudnik-Schoneborn S, Blaschek A, Wolf NI, Harting I, North K, Smith J, Muntoni F, Brockington M, Quijano-Roy S, Renault F, Herrmann R, Hendershot LM, Schroder JM, Lochmuller H, Topaloglu H, Voit T, Weis J, Ebinger F, Zerres K. Mutations in SIL1 cause Marinesco-Sjogren syndrome, a cerebellar ataxia with cataract and myopathy. Nat Genet 37: 1312–1314, 2005.[CrossRef][Web of Science][Medline]
344. Shen Y, Hendershot LM. ERdj3, a stress-inducible endoplasmic reticulum DnaJ homologue, serves as a cofactor for BiP's interactions with unfolded substrates. Mol Biol Cell 16: 40–50, 2005.[Abstract/Free Full Text]
345. Shen Y, Meunier L, Hendershot LM. Identification and characterization of a novel endoplasmic reticulum (ER) DnaJ homologue, which stimulates ATPase activity of BiP in vitro and is induced by ER stress. J Biol Chem 277: 15947–15956, 2002.[Abstract/Free Full Text]
346. Shibatani T, David LL, McCormack AL, Frueh K, Skach WR. Proteomic analysis of mammalian oligosaccharyltransferase reveals multiple subcomplexes that contain Sec61, TRAP, two potential new subunits. Biochemistry 44: 5982–5992, 2005.[CrossRef][Medline]
347. Shiu RP, Pouyssegur J, Pastan I. Glucose depletion accounts for the induction of two transformation-sensitive membrane proteins in Rous sarcoma virus-transformed chick embryo fibroblasts. Proc Natl Acad Sci USA 74: 3840–3844, 1977.[Abstract/Free Full Text]
348. Sitia R, Neuberger MS, Milstein C. Regulation of membrane IgM expression in secretory B cells: translational and post-translational events. EMBO J 6: 3969–3977, 1987.[Web of Science][Medline]
349. Skowronek MH, Rotter M, Haas IG. Molecular characterization of a novel mammalian DnaJ-like Sec63p homolog. Biol Chem 380: 1133–1138, 1999.[CrossRef][Web of Science][Medline]
350. Smith T, Ferreira LR, Hebert C, Norris K, Sauk JJ. Hsp47 and cyclophilin B traverse the endoplasmic reticulum with procollagen into pre-Golgi intermediate vesicles. A role for Hsp47 and cyclophilin B in the export of procollagen from the endoplasmic reticulum. J Biol Chem 270: 18323–18328, 1995.[Abstract/Free Full Text]
351. Soldà T, Garbi N, Hammerling GJ, Molinari M. Consequences of ERp57 deletion on oxidative folding of obligate and facultative clients of the calnexin cycle. J Biol Chem 281: 6219–6226, 2006.[Abstract/Free Full Text]
351. Soldà T, Galli C, Kaufman RJ, Molinari M. Substrate-specific requirements for UGT1-dependent release from calnexin. Mol Cell 27: 238–249, 2007.[CrossRef][Web of Science][Medline]
352. Soldano KL, Jivan A, Nicchitta CV, Gewirth DT. Structure of the N-terminal domain of GRP94. Basis for ligand specificity and regulation. J Biol Chem 278: 48330–48338, 2003.[Abstract/Free Full Text]
353. Sommer T, Jentsch S. A protein translocation defect linked to ubiquitin conjugation at the endoplasmic reticulum. Nature 365: 176–179, 1993.[CrossRef][Medline]
354. Sorgjerd K, Ghafouri B, Jonsson BH, Kelly JW, Blond SY, Hammarstrom P. Retention of misfolded mutant transthyretin by the chaperone BiP/GRP78 mitigates amyloidogenesis. J Mol Biol 356: 469–482, 2006.[CrossRef][Web of Science][Medline]
355. Sousa M, Parodi AJ. The molecular basis for the recognition of misfolded glycoproteins by the UDP-Glc:glycoprotein glucosyltransferase. EMBO J 14: 4196–4203, 1995.[Web of Science][Medline]
356. Spiro RG, Zhu Q, Bhoyroo V, Soling HD. Definition of the lectin-like properties of the molecular chaperone, calreticulin, demonstration of its copurification with endomannosidase from rat liver Golgi. J Biol Chem 271: 11588–11594, 1996.[Abstract/Free Full Text]
357. Srivastava SP, Chen NQ, Liu YX, Holtzman JL. Purification and characterization of a new isozyme of thiol:protein-disulfide oxidoreductase from rat hepatic microsomes. Relationship of this isozyme to cytosolic phosphatidylinositol-specific phospholipase C form 1A. J Biol Chem 266: 20337–20344, 1991.[Abstract/Free Full Text]
358. Steel GJ, Fullerton DM, Tyson JR, Stirling CJ. Coordinated activation of Hsp70 chaperones. Science 303: 98–101, 2004.[Abstract/Free Full Text]
359. Su K, Stoller T, Rocco J, Zemsky J, Green R. Pre-Golgi degradation of yeast prepro-alpha-factor expressed in a mammalian cell. Influence of cell type-specific oligosaccharide processing on intracellular fate. J Biol Chem 268: 14301–14309, 1993.[Abstract/Free Full Text]
360. Supino-Rosin L, Yoshimura A, Yarden Y, Elazar Z, Neumann D. Intracellular retention and degradation of the epidermal growth factor receptor, two distinct processes mediated by benzoquinone ansamycins. J Biol Chem 275: 21850–21855, 2000.[Abstract/Free Full Text]
361. Suzuki CK, Bonifacino JS, Lin AY, Davis MM, Klausner RD. Regulating the retention of T-cell receptor alpha chain variants within the endoplasmic reticulum: Ca²⁺-dependent association with BiP. J Cell Biol 114: 189–205, 1991.[Abstract/Free Full Text]
362. Suzuki T, Park H, Hollingsworth NM, Sternglanz R, Lennarz WJ. PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase. J Cell Biol 149: 1039–1052, 2000.[Abstract/Free Full Text]
363. Svedine S, Wang T, Halaban R, Hebert DN. Carbohydrates act as sorting determinants in ER-associated degradation of tyrosinase. J Cell Sci 117: 2937–2949, 2004.[Abstract/Free Full Text]
364. Swan D, Aviv H, Leder P. Purification and properties of biologically active messenger RNA for a myeloma light chain. Proc Natl Acad Sci USA 69: 1967–1971, 1972.[Abstract/Free Full Text]
365. Swanton E, High S. ER targeting signals: more than meets the eye? Cell 127: 877–879, 2006.[CrossRef][Web of Science][Medline]
366. Tamarappoo BK, Verkman AS. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones. J Clin Invest 101: 2257–2267, 1998.[Web of Science][Medline]
367. Taylor SC, Ferguson AD, Bergeron JJ, Thomas DY. The ER protein folding sensor UDP-glucose glycoprotein-glucosyltransferase modifies substrates distant to local changes in glycoprotein conformation. Nat Struct Mol Biol 11: 128–134, 2004.[CrossRef][Web of Science][Medline]
368. Tempel W, Karaveg K, Liu ZJ, Rose J, Wang BC, Moremen KW. Structure of mouse Golgi -mannosidase IA reveals the molecular basis for substrate specificity among class 1 (family 47 glycosylhydrolase) 1,2-mannosidases. J Biol Chem 279: 29774–29786, 2004.[Abstract/Free Full Text]
369. Tian G, Xiang S, Noiva R, Lennarz WJ, Schindelin H. The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites. Cell 124: 61–73, 2006.[CrossRef][Web of Science][Medline]
370. Tirosh B, Furman MH, Tortorella D, Ploegh HL. Protein unfolding is not a prerequisite for endoplasmic reticulum-to-cytosol dislocation. J Biol Chem 278: 6664–6672, 2003.[Abstract/Free Full Text]
371. Tokunaga F, Tsukamoto T, Koide T. Cellular basis for protein C deficiency caused by a single amino acid substitution at Arg15 in the gamma-carboxyglutamic acid domain. J Biochem 120: 360–368, 1996.[Abstract/Free Full Text]
372. Tolleshaug H, Hobgood KK, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor. Cell 32: 941–951, 1983.[CrossRef][Web of Science][Medline]
373. Tomita Y, Yamashita T, Sato H, Taira H. Kinetics of interactions of sendai virus envelope glycoproteins, F and HN, with endoplasmic reticulum-resident molecular chaperones, BiP, calnexin, calreticulin. J Biochem 126: 1090–1100, 1999.[Abstract/Free Full Text]
374. Tonegawa S, Baldi I. Electrophoretically homogeneous myeloma light chain mRNA and its translation in vitro. Biochem Biophys Res Commun 51: 81–87, 1973.[CrossRef][Web of Science][Medline]
375. Totani K, Ihara Y, Matsuo I, Ito Y. Substrate specificity analysis of endoplasmic reticulum glucosidase II using synthetic high-mannose-type glycans. J Biol Chem 281: 31502–31508, 2006.[Abstract/Free Full Text]
376. Townsend A, Ohlen C, Bastin J, Ljunggren HG, Foster L, Karre K. Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nature 340: 443–448, 1989.[CrossRef][Medline]
377. Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101: 249–258, 2000.[CrossRef][Web of Science][Medline]
378. Trombetta ES, Fleming KG, Helenius A. Quaternary and domain structure of glycoprotein processing glucosidase II. Biochemistry 40: 10717–10722, 2001.[CrossRef][Medline]
379. Trombetta ES, Simons JF, Helenius A. Endoplasmic reticulum glucosidase II is composed of a catalytic subunit, conserved from yeast to mammals, a tightly bound noncatalytic HDEL-containing subunit. J Biol Chem 271: 27509–27516, 1996.[Abstract/Free Full Text]
380. Tu BP, Weissman JS. Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol 164: 341–346, 2004.[Abstract/Free Full Text]
381. Turner GC, Varshavsky A. Detecting and measuring cotranslational protein degradation in vivo. Science 289: 2117–2120, 2000.[Abstract/Free Full Text]
382. Tyedmers J, Lerner M, Bies C, Dudek J, Skowronek MH, Haas IG, Heim N, Nastainczyk W, Volkmer J, Zimmermann R. Homologs of the yeast Sec complex subunits Sec62p and Sec63p are abundant proteins in dog pancreas microsomes. Proc Natl Acad Sci USA 97: 7214–7219, 2000.[Abstract/Free Full Text]
383. Vabulas RM, Hartl FU. Protein synthesis upon acute nutrient restriction relies on proteasome function. Science 310: 1960–1963, 2005.[Abstract/Free Full Text]
384. Vahdati-Ben Arieh S, Laham N, Schechter C, Yewdell JW, Coligan JE, Ehrlich R. A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules. Blood 101: 2858–2864, 2003.[Abstract/Free Full Text]
385. Van den Berg B, Clemons WM Jr, Collinson I, Modis Y, Hartmann E, Harrison SC, Rapoport TA. X-ray structure of a protein-conducting channel. Nature 427: 36–44, 2004.[CrossRef][Medline]
386. VanSlyke JK, Deschenes SM, Musil LS. Intracellular transport, assembly, degradation of wild-type and disease-linked mutant gap junction proteins. Mol Biol Cell 11: 1933–1946, 2000.[Abstract/Free Full Text]
387. Varon R, Magdorf K, Staab D, Wahn HU, Krawczak M, Sperling K, Reis A. Recurrent nasal polyps as a monosymptomatic form of cystic fibrosis associated with a novel in-frame deletion (591del18) in the CFTR gene. Hum Mol Genet 4: 1463–1464, 1995.[Free Full Text]
388. Vashist S, Ng DT. Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J Cell Biol 165: 41–52, 2004.[Abstract/Free Full Text]
389. Veijola J, Pettersson RF. Transient association of calnexin and calreticulin with newly synthesized G1 and G2 glycoproteins of uukuniemi virus (family Bunyaviridae). J Virol 73: 6123–6127, 1999.[Abstract/Free Full Text]
390. Venetianer P, Straub FB. The enzymic reactivation of reduced ribonuclease. Biochim Biophys Acta 67: 166–168, 1963.[Medline]
391. Verpy E, Couture-Tosi E, Tosi M. C1 inhibitor mutations which affect intracellular transport and secretion in type I hereditary angioedema. Behring Inst Mitt: 120–124, 1993.
392. Vij N, Fang S, Zeitlin PL. Selective inhibition of endoplasmic reticulum-associated degradation rescues DeltaF508-cystic fibrosis transmembrane regulator and suppresses interleukin-8 levels: therapeutic implications. J Biol Chem 281: 17369–17378, 2006.[Abstract/Free Full Text]
393. Wada I, Imai S, Kai M, Sakane F, Kanoh H. Chaperone function of calreticulin when expressed in the endoplasmic reticulum as the membrane-anchored and soluble forms. J Biol Chem 270: 20298–20304, 1995.[Abstract/Free Full Text]
394. Wada I, Ou WJ, Liu MC, Scheele G. Chaperone function of calnexin for the folding intermediate of gp80, the major secretory protein in MDCK cells. Regulation by redox state and ATP. J Biol Chem 269: 7464–7472, 1994.[Abstract/Free Full Text]
395. Wada I, Rindress D, Cameron PH, Ou WJ, Doherty JJ II, Louvard D, Bell AW, Dignard D, Thomas DY, Bergeron JJM. SSRalpha and associated calnexin are major calcium binding proteins of the endoplasmic reticulum membrane. J Biol Chem 266: 19599–19610, 1991.[Abstract/Free Full Text]
396. Walter J, Urban J, Volkwein C, Sommer T. Sec61p-independent degradation of the tail-anchored ER membrane protein Ubc6p. EMBO J 20: 3124–3131, 2001.[CrossRef][Web of Science][Medline]
397. Walter P, Blobel G. Purification of a membrane-associated protein complex required for protein translocation across the endoplasmic reticulum. Proc Natl Acad Sci USA 77: 7112–7116, 1980.[Abstract/Free Full Text]
398. Walter P, Blobel G. Signal recognition particle contains a 7S RNA essential for protein translocation across the endoplasmic reticulum. Nature 299: 691–698, 1982.[CrossRef][Medline]
399. Walter P, Blobel G. Translocation of proteins across the endoplasmic reticulum. III. Signal recognition protein (SRP) causes signal sequence-dependent and site-specific arrest of chain elongation that is released by microsomal membranes. J Cell Biol 91: 557–561, 1981.[Abstract/Free Full Text]
400. Wang N, Daniels R, Hebert DN. The cotranslational maturation of the type I membrane glycoprotein tyrosinase: the heat shock protein 70 system hands off to the lectin-based chaperone system. Mol Biol Cell 16: 3740–3752, 2005.[Abstract/Free Full Text]
401. Wang Y, Han R, Wu D, Li J, Chen C, Ma H, Mi H. The binding of FKBP23 to BiP modulates BiP's ATPase activity with its PPIase activity. Biochem Biophys Res Commun 354: 315–320, 2007.[CrossRef][Web of Science][Medline]
402. Ward CL, Kopito RR. Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins. J Biol Chem 269: 25710–25718, 1994.[Abstract/Free Full Text]
403. Ward CL, Omura S, Kopito RR. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83: 121–127, 1995.[CrossRef][Web of Science][Medline]
404. Weihl CC, Dalal S, Pestronk A, Hanson PI. Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum Mol Genet 15: 189–199, 2006.[Abstract/Free Full Text]
405. Weitzmann A, Volkmer J, Zimmermann R. The nucleotide exchange factor activity of Grp170 may explain the non-lethal phenotype of loss of Sil1 function in man and mouse. FEBS Lett 580: 5237–5240, 2006.[CrossRef][Web of Science][Medline]
406. Werner ED, Brodsky JL, McCracken AA. Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc Natl Acad Sci USA 93: 13797–13801, 1996.[Abstract/Free Full Text]
407. White FH Jr. Regeneration of native secondary and tertiary structures by air oxidation of reduced ribonuclease. J Biol Chem 236: 1353–1360, 1961.[Free Full Text]
408. Whiteman P, Handford PA. Defective secretion of recombinant fragments of fibrillin-1: implications of protein misfolding for the pathogenesis of Marfan syndrome and related disorders. Hum Mol Genet 12: 727–737, 2003.[Abstract/Free Full Text]
409. Whitley P, Nilsson IM, von Heijne G. A nascent secretory protein may traverse the ribosome/endoplasmic reticulum translocase complex as an extended chain. J Biol Chem 271: 6241–6244, 1996.[Abstract/Free Full Text]
410. Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84: 769–779, 1996.[CrossRef][Web of Science][Medline]
411. Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR, Rapoport TA, Ploegh HL. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384: 432–438, 1996.[CrossRef][Medline]
412. Wilkinson BM, Purswani J, Stirling CJ. Yeast GTB1 encodes a subunit of glucosidase II required for glycoprotein processing in the endoplasmic reticulum. J Biol Chem 281: 6325–6333, 2006.[Abstract/Free Full Text]
413. Willey RL, Maldarelli F, Martin MA, Strebel K. Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J Virol 66: 7193–7200, 1992.[Abstract/Free Full Text]
414. Williams DB. Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum. J Cell Sci 119: 615–623, 2006.[Abstract/Free Full Text]
415. Witzig TE, Wahner-Roedler DL. Heavy chain disease. Curr Treat Options Oncol 3: 247–254, 2002.[CrossRef][Medline]
416. Wojcik J, Berg MA, Esposito N, Geffner ME, Sakati N, Reiter EO, Dower S, Francke U, Postel-Vinay MC, Finidori J. Four contiguous amino acid substitutions, identified in patients with Laron syndrome, differently affect the binding affinity and intracellular trafficking of the growth hormone receptor. J Clin Endocrinol Metab 83: 4481–4489, 1998.[Abstract/Free Full Text]
417. Wojcikiewicz RJ, Xu Q, Webster JM, Alzayady K, Gao C. Ubiquitination and proteasomal degradation of endogenous and exogenous inositol 1,4,5-trisphosphate receptors in alpha T3–1 anterior pituitary cells. J Biol Chem 278: 940–947, 2003.[Abstract/Free Full Text]
418. Wolf DH, Schafer A. CPY* and the power of yeast genetics in the elucidation of quality control and associated protein degradation of the endoplasmic reticulum. Curr Top Microbiol Immunol 300: 41–56, 2005.[Web of Science][Medline]
419. Woolhead CA, McCormick PJ, Johnson AE. Nascent membrane and secretory proteins differ in FRET-detected folding far inside the ribosome and in their exposure to ribosomal proteins. Cell 116: 725–736, 2004.[CrossRef][Web of Science][Medline]
420. Wu Y, Swulius MT, Moremen KW, Sifers RN. Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation. Proc Natl Acad Sci USA 100: 8229–8234, 2003.[Abstract/Free Full Text]
421. Xie Q, Khaoustov VI, Chung CC, Sohn J, Krishnan B, Lewis DE, Yoffe B. Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation. Hepatology 36: 592–601, 2002.[CrossRef][Web of Science][Medline]
422. Ye Y, Meyer HH, Rapoport TA. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414: 652–656, 2001.[CrossRef][Medline]
423. Ye Y, Shibata Y, Kikkert M, van Voorden S, Wiertz E, Rapoport TA. Inaugural Article: recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane. Proc Natl Acad Sci USA 102: 14132–14138, 2005.[Abstract/Free Full Text]
424. Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429: 841–847, 2004.[CrossRef][Medline]
425. York IA, Mo AX, Lemerise K, Zeng W, Shen Y, Abraham CR, Saric T, Goldberg AL, Rock KL. The cytosolic endopeptidase, thimet oligopeptidase, destroys antigenic peptides and limits the extent of MHC class I antigen presentation. Immunity 18: 429–440, 2003.[CrossRef][Web of Science][Medline]
426. York J, Romanowski V, Lu M, Nunberg JH. The signal peptide of the Junin arenavirus envelope glycoprotein is myristoylated and forms an essential subunit of the mature G₁–G₂ complex. J Virol 78: 10783–10792, 2004.[Abstract/Free Full Text]
427. Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K, Mori K. A time-dependent phase shift in the mammalian unfolded protein response. Dev Cell 4: 265–271, 2003.[CrossRef][Web of Science][Medline]
428. Yoshida H, Oku M, Suzuki M, Mori K. pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response. J Cell Biol 172: 565–575, 2006.
429. Yoshida Y, Adachi E, Fukiya K, Iwai K, Tanaka K. Glycoprotein-specific ubiquitin ligases recognize N-glycans in unfolded substrates. EMBO Rep 6: 239–244, 2005.[CrossRef][Web of Science][Medline]
430. Yoshida Y, Chiba T, Tokunaga F, Kawasaki H, Iwai K, Suzuki T, Ito Y, Matsuoka K, Yoshida M, Tanaka K, Tai T. E3 ubiquitin ligase that recognizes sugar chains. Nature 418: 438–442, 2002.[CrossRef][Medline]
431. Yoshida Y, Murakami A, Iwai K, Tanaka K. A neural-specific F-box protein FBS1 functions as a chaperone suppressing glycoprotein aggregation. J Biol Chem. In press.
432. Yu M, Haslam RH, Haslam DB. HEDJ, an Hsp40 co-chaperone localized to the endoplasmic reticulum of human cells. J Biol Chem 275: 24984–24992, 2000.[Abstract/Free Full Text]
433. Zapun A, Darby NJ, Tessier DC, Michalak M, Bergeron JJ, Thomas DY. Enhanced catalysis of ribonuclease B folding by the interaction of calnexin or calreticulin with ERp57. J Biol Chem 273: 6009–6012, 1998.[Abstract/Free Full Text]
434. Zeitlin PL, Diener-West M, Rubenstein RC, Boyle MP, Lee CK, Brass-Ernst L. Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Mol Ther 6: 119–126, 2002.[CrossRef][Web of Science][Medline]
435. Zhang J, Herscovitz H. Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, cyclophilin B. J Biol Chem 278: 7459–7468, 2003.[Abstract/Free Full Text]
436. Zhang X, Wang Y, Li H, Zhang W, Wu D, Mi H. The mouse FKBP23 binds to BiP in ER and the binding of C-terminal domain is interrelated with Ca²⁺ concentration. FEBS Lett 559: 57–60, 2004.[CrossRef][Web of Science][Medline]
437. Zhou M, Schekman R. The engagement of Sec61p in the ER dislocation process. Mol Cell 4: 925–934, 1999.[CrossRef][Web of Science][Medline]
438. Zuber C, Cormier JH, Guhl B, Santimaria R, Hebert DN, Roth J. EDEM1 reveals a quality control vesicular transport pathway out of the endoplasmic reticulum not involving the COPII exit sites. Proc Natl Acad Sci USA 104: 4407–4412, 2007.[Abstract/Free Full Text]

This article has been cited by other articles:

				R. P Quinn, S. J Mahoney, B. M Wilkinson, D. J Thornton, and C. J Stirling A novel role for Gtb1p in glucose trimming of N-linked glycans Glycobiology, December 1, 2009; 19(12): 1408 - 1416. [Abstract] [Full Text] [PDF]

				P. Roboti, E. Swanton, and S. High Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein J. Cell Sci., November 1, 2009; 122(21): 3942 - 3953. [Abstract] [Full Text] [PDF]

				P. J. Lim, R. Danner, J. Liang, H. Doong, C. Harman, D. Srinivasan, C. Rothenberg, H. Wang, Y. Ye, S. Fang, et al. Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD J. Cell Biol., October 19, 2009; 187(2): 201 - 217. [Abstract] [Full Text] [PDF]

				S. D. Whitman, E. C. Smith, and R. E. Dutch Differential Rates of Protein Folding and Cellular Trafficking for the Hendra Virus F and G Proteins: Implications for F-G Complex Formation J. Virol., September 1, 2009; 83(17): 8998 - 9001. [Abstract] [Full Text] [PDF]

				J. Cui, T. Smith, P. W. Robbins, and J. Samuelson Darwinian selection for sites of Asn-linked glycosylation in phylogenetically disparate eukaryotes and viruses PNAS, August 11, 2009; 106(32): 13421 - 13426. [Abstract] [Full Text] [PDF]

				N. Zaarour, S. Demaretz, N. Defontaine, D. Mordasini, and K. Laghmani A Highly Conserved Motif at the COOH Terminus Dictates Endoplasmic Reticulum Exit and Cell Surface Expression of NKCC2 J. Biol. Chem., August 7, 2009; 284(32): 21752 - 21764. [Abstract] [Full Text] [PDF]

				E. White, J. McKenna, A. Cavanaugh, and G. E. Breitwieser Pharmacochaperone-Mediated Rescue of Calcium-Sensing Receptor Loss-of-Function Mutants Mol. Endocrinol., July 1, 2009; 23(7): 1115 - 1123. [Abstract] [Full Text] [PDF]

				M. H. Doolittle, O. Ben-Zeev, S. Bassilian, J. P. Whitelegge, M. Peterfy, and H. Wong Hepatic lipase maturation: a partial proteome of interacting factors J. Lipid Res., June 1, 2009; 50(6): 1173 - 1184. [Abstract] [Full Text] [PDF]

				P. B. Beauregard, R. Guerin, C. Turcotte, S. Lindquist, and L. A. Rokeach A nucleolar protein allows viability in the absence of the essential ER-residing molecular chaperone calnexin J. Cell Sci., May 1, 2009; 122(9): 1342 - 1351. [Abstract] [Full Text] [PDF]

				A. Mishra, S. K. Godavarthi, M. Maheshwari, A. Goswami, and N. R. Jana The Ubiquitin Ligase E6-AP Is Induced and Recruited to Aggresomes in Response to Proteasome Inhibition and May Be Involved in the Ubiquitination of Hsp70-bound Misfolded Proteins J. Biol. Chem., April 17, 2009; 284(16): 10537 - 10545. [Abstract] [Full Text] [PDF]

				D. J. Termine, K. W. Moremen, and R. N. Sifers The mammalian UPR boosts glycoprotein ERAD by suppressing the proteolytic downregulation of ER mannosidase I J. Cell Sci., April 1, 2009; 122(7): 976 - 984. [Abstract] [Full Text] [PDF]

				M. C. Jonikas, S. R. Collins, V. Denic, E. Oh, E. M. Quan, V. Schmid, J. Weibezahn, B. Schwappach, P. Walter, J. S. Weissman, et al. Comprehensive Characterization of Genes Required for Protein Folding in the Endoplasmic Reticulum Science, March 27, 2009; 323(5922): 1693 - 1697. [Abstract] [Full Text] [PDF]

				O. Vagin, J. A. Kraut, and G. Sachs Role of N-glycosylation in trafficking of apical membrane proteins in epithelia Am J Physiol Renal Physiol, March 1, 2009; 296(3): F459 - F469. [Abstract] [Full Text] [PDF]

				L. Zhang, E. Lai, T. Teodoro, and A. Volchuk GRP78, but Not Protein-disulfide Isomerase, Partially Reverses Hyperglycemia-induced Inhibition of Insulin Synthesis and Secretion in Pancreatic {beta}-Cells J. Biol. Chem., February 20, 2009; 284(8): 5289 - 5298. [Abstract] [Full Text] [PDF]

				L. Izquierdo, A. Atrih, J. A. Rodrigues, D. C. Jones, and M. A. J. Ferguson Trypanosoma brucei UDP-Glucose:Glycoprotein Glucosyltransferase Has Unusual Substrate Specificity and Protects the Parasite from Stress Eukaryot. Cell, February 1, 2009; 8(2): 230 - 240. [Abstract] [Full Text] [PDF]

				G. L. Vilas, D. E. Johnson, P. Freund, and J. R. Casey Characterization of an epilepsy-associated variant of the human Cl-/HCOFormula exchanger AE3 Am J Physiol Cell Physiol, January 1, 2009; 297(3): C526 - C536. [Abstract] [Full Text] [PDF]

				N. Wang, E. J. Glidden, S. R. Murphy, B. R. Pearse, and D. N. Hebert The Cotranslational Maturation Program for the Type II Membrane Glycoprotein Influenza Neuraminidase J. Biol. Chem., December 5, 2008; 283(49): 33826 - 33837. [Abstract] [Full Text] [PDF]

				M. H. Brush and S. Shenolikar Control of Cellular GADD34 Levels by the 26S Proteasome Mol. Cell. Biol., December 1, 2008; 28(23): 6989 - 7000. [Abstract] [Full Text] [PDF]

				C.-H. Chan, H. M. Mitchison, and D. A. Pearce Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models Hum. Mol. Genet., November 1, 2008; 17(21): 3332 - 3339. [Abstract] [Full Text] [PDF]

				O. Vanoni, P. Paganetti, and M. Molinari Consequences of Individual N-glycan Deletions and of Proteasomal Inhibition on Secretion of Active BACE Mol. Biol. Cell, October 1, 2008; 19(10): 4086 - 4098. [Abstract] [Full Text] [PDF]

				A. Ashok and R. S. Hegde Retrotranslocation of Prion Proteins from the Endoplasmic Reticulum by Preventing GPI Signal Transamidation Mol. Biol. Cell, August 1, 2008; 19(8): 3463 - 3476. [Abstract] [Full Text] [PDF]

				R. Bernasconi, T. Pertel, J. Luban, and M. Molinari A Dual Task for the Xbp1-responsive OS-9 Variants in the Mammalian Endoplasmic Reticulum: INHIBITING SECRETION OF MISFOLDED PROTEIN CONFORMERS AND ENHANCING THEIR DISPOSAL J. Biol. Chem., June 13, 2008; 283(24): 16446 - 16454. [Abstract] [Full Text] [PDF]

				B. R. Pearse, L. Gabriel, N. Wang, and D. N. Hebert A cell-based reglucosylation assay demonstrates the role of GT1 in the quality control of a maturing glycoprotein J. Cell Biol., April 21, 2008; 181(2): 309 - 320. [Abstract] [Full Text] [PDF]

				L. Abrami, B. Kunz, I. Iacovache, and F. G. van der Goot Palmitoylation and ubiquitination regulate exit of the Wnt signaling protein LRP6 from the endoplasmic reticulum PNAS, April 8, 2008; 105(14): 5384 - 5389. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (54) Citing Articles via Google Scholar Google Scholar Articles by Hebert, D. N. Articles by Molinari, M. Search for Related Content PubMed PubMed Citation Articles by Hebert, D. N. Articles by Molinari, M.