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Physiological Reviews, Vol. 82, No. 2, April 2002, pp. 373-428; 10.1152/physrev.00027.2001.
Copyright ©2002 by the American Physiological Society
Faculty of Biology and the Institute for Catalysis Science and Technology, and Department of Biochemistry, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Glickman, Michael H. and
Aaron Ciechanover.
The Ubiquitin-Proteasome Proteolytic Pathway: Destruction
for the Sake of Construction. Physiol. Rev. 82: 373-428, 2002.
Between the 1960s and 1980s, most life
scientists focused their attention on studies of nucleic acids and the
translation of the coded information. Protein degradation was a
neglected area, considered to be a nonspecific, dead-end process.
Although it was known that proteins do turn over, the large extent and high specificity of the process, whereby distinct proteins have half-lives that range from a few minutes to several days, was not
appreciated. The discovery of the lysosome by Christian de Duve did not
significantly change this view, because it became clear that this
organelle is involved mostly in the degradation of extracellular
proteins, and their proteases cannot be substrate specific. The
discovery of the complex cascade of the ubiquitin pathway
revolutionized the field. It is clear now that degradation of cellular
proteins is a highly complex, temporally controlled, and tightly
regulated process that plays major roles in a variety of basic pathways
during cell life and death as well as in health and disease. With the
multitude of substrates targeted and the myriad processes involved, it
is not surprising that aberrations in the pathway are implicated in the
pathogenesis of many diseases, certain malignancies, and
neurodegeneration among them. Degradation of a protein via the
ubiquitin/proteasome pathway involves two successive steps:
1) conjugation of multiple ubiquitin moieties to the
substrate and 2) degradation of the tagged protein by the downstream 26S proteasome complex. Despite intensive research, the
unknown still exceeds what we currently know on intracellular protein
degradation, and major key questions have remained unsolved. Among
these are the modes of specific and timed recognition for the
degradation of the many substrates and the mechanisms that underlie
aberrations in the system that lead to pathogenesis of diseases.
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