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Physiological Reviews, Vol. 80, No. 4, October 2000, pp. 1483-1521
Copyright ©2000 by the American Physiological Society
Section of Hematology Research and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota; and Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts
Rusnak, Frank and
Pamela Mertz.
Calcineurin: Form and Function. Physiol. Rev. 80: 1483-1521, 2000.
Calcineurin is
a eukaryotic Ca2+- and calmodulin-dependent
serine/threonine protein phosphatase. It is a heterodimeric protein consisting of a catalytic subunit calcineurin A, which contains an
active site dinuclear metal center, and a tightly associated, myristoylated, Ca2+-binding subunit, calcineurin B. The
primary sequence of both subunits and heterodimeric quaternary
structure is highly conserved from yeast to mammals. As a
serine/threonine protein phosphatase, calcineurin participates in a
number of cellular processes and Ca2+-dependent signal
transduction pathways. Calcineurin is potently inhibited by
immunosuppressant drugs, cyclosporin A and FK506, in the presence of
their respective cytoplasmic immunophilin proteins, cyclophilin and
FK506-binding protein. Many studies have used these immunosuppressant
drugs and/or modern genetic techniques to disrupt calcineurin in model
organisms such as yeast, filamentous fungi, plants, vertebrates, and
mammals to explore its biological function. Recent advances regarding
calcineurin structure include the determination of its
three-dimensional structure. In addition, biochemical and
spectroscopic studies are beginning to unravel aspects of the mechanism
of phosphate ester hydrolysis including the importance of the dinuclear
metal ion cofactor and metal ion redox chemistry, studies which may
lead to new calcineurin inhibitors. This review provides a
comprehensive examination of the biological roles of calcineurin and
reviews aspects related to its structure and catalytic mechanism.
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