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Frank Rusnak and Pamela Mertz Physiol Rev 80:1483-1521, 2000 Frank Rusnak and Pamela Mertz Physiol Rev 80:1483-1521, 2000. You might find this additional information useful... This article cites 468 articles, 186 of which you can access free at: http://physrev.physiology.org/cgi/content/full/80/4/1483#BIBL This article has been cited by 96 other HighWire hosted articles, the first 5 are: Calcineurin-Responsive Zinc Finger Transcription Factor CRZ1 of Botrytis cinerea Is Required for Growth, Development, and Full Virulence on Bean Plants J. Schumacher, I. F. de Larrinoa and B. Tudzynski Eukaryot. Cell, April 1, 2008; 7 (4): 584-601. [Abstract] [Full Text] [PDF] Inactivation of Host Akt/Protein Kinase B Signaling by Bacterial Pore-forming Toxins T. J. Wiles, B. K. Dhakal, D. S. Eto and M. A. Mulvey Mol. Biol. Cell, April 1, 2008; 19 (4): 1427-1438. [Abstract] [Full Text] [PDF] Calcineurin Regulation in Fungi and Beyond J. Stie and D. Fox Downloaded from Eukaryot. Cell, February 1, 2008; 7 (2): 177-186. [Full Text] [PDF] Characterization of the 2',3' cyclic phosphodiesterase activities of Clostridium thermocellum polynucleotide kinase-phosphatase and bacteriophage {lambda} phosphatase N. Keppetipola and S. Shuman physrev.physiology.org Nucleic Acids Res., December 3, 2007; 35 (22): 7721-7732. [Abstract] [Full Text] [PDF] Developmental regulation of calcineurin isoforms in the rodent kidney: association with COX-2 H. Liu, W. Ye, G. Guan, Z. Dong, Z. Jia and T. Yang Am J Physiol Renal Physiol, December 1, 2007; 293 (6): F1898-F1904. [Abstract] [Full Text] [PDF] on April 15, 2008 Medline items on this article's topics can be found at http://highwire.stanford.edu/lists/artbytopic.dtl on the following topics: Oncology .. Cyclophilins Biochemistry .. Phosphatases Biochemistry .. Phosphoprotein Phosphatase Biochemistry .. Enzyme Active Site Cell Biology .. Cytoplasm Chemistry .. Metal Ions Updated information and services including high-resolution figures, can be found at: http://physrev.physiology.org/cgi/content/full/80/4/1483 Additional material and information about Physiological Reviews can be found at: http://www.the-aps.org/publications/prv This information is current as of April 15, 2008 . Physiological Reviews provides state of the art coverage of timely issues in the physiological and biomedical sciences. It is published quarterly in January, April, July, and October by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society. ISSN: 0031-9333, ESSN: 1522-1210. Visit our website at http://www.the-aps.org/. PHYSIOLOGICAL REVIEWS Vol. 80, No. 4, October 2000 Printed in U.S.A. Calcineurin: Form and Function FRANK RUSNAK AND PAMELA MERTZ 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 I. Introduction 1483 II. A Brief History and Overview of Calcineurin 1484 A. Calcineurin: the early years 1484 B. Calcineurin properties 1484 Downloaded from III. Physiological Roles for Calcineurin 1490 A. Lower eukaryotes 1490 B. Higher eukaryotes 1494 C. Inhibitors of calcineurin 1497 IV. Calcineurin Structure 1500 A. A dinuclear metal-binding phosphoesterase motif 1500 B. Three-dimensional structure 1500 C. Active site architecture 1502 physrev.physiology.org D. Metal ion requirements 1503 V. Enzymatic Mechanism 1504 A. Mechanism of phosphoryl group transfer: evidence for direct transfer to water 1504 B. Catalytic role of the dinuclear metal center 1505 C. Conserved active site residues 1505 D. A model for the calcineurin catalytic mechanism 1508 VI. Regulation 1510 on April 15, 2008 Rusnak, Frank, and Pamela Mertz. Calcineurin: Form and Function. Physiol Rev 80: 1483–1521, 2000.—Cal- cineurin is a eukaryotic Ca2ϩ- 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, Ca2ϩ-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 Ca2ϩ-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. I. INTRODUCTION dependent phosphodiesterase (444) to the ground-breaking discovery that it is the target of the immunosuppressant The year 1999 marked the 20th anniversary of the drugs cyclosporin A (CsA) and FK506, pharmacological re- isolation of the Ca2ϩ- and calmodulin-dependent protein agents that have been used to demonstrate it as a major serine/threonine phosphatase calcineurin (206). During player in Ca2ϩ-dependent eukaryotic signal transduction the past 20 years, the biological roles of calcineurin have pathways (238). In recent years, several milestones regard- progressed from a putative inhibitor of the calmodulin- ing calcineurin structure have been achieved including the http://physrev.physiology.org 0031-9333/00 $15.00 Copyright © 2000 the American Physiological Society 1483 1484 FRANK RUSNAK AND PAMELA MERTZ Volume 80 determination of the three-dimensional structure by X-ray dependent cyclic nucleotide phosphodiesterase. Indepen- diffraction methods (124, 197) and biochemical, spectro- dently, Watterson and Vanaman (452) also obtained scopic, and physical studies that are beginning to unravel its highly purified fractions of calcineurin from bovine brain catalytic mechanism (150, 259, 261, 262, 470, 471). Insight extract by use of calmodulin-affinity chromatography but into its physiological functions include mapping its subcel- erroneously referred to the 58- and 18-kDa subunits of lular localization (10, 106, 175, 219, 286, 306); the discovery calcineurin as “affinity-purified phosphodiesterase.” Klee of its colocalization with other important signaling proteins and Krinks (206) are credited with the first purification of (365); and, aside from Ca2ϩ/calmodulin, the finding of pos- calcineurin and hypothesized that it might be a regulatory sible endogenous regulators of its activity including redox subunit of phosphodiesterase since it was demonstrated and/or oxidative stress (45, 111, 345, 447, 470, 471) as well as to inhibit phosphodiesterase activity. Other groups sub- interacting proteins (224, 234, 277, 359, 400). The next gen- sequently showed that calcineurin inhibited the Ca2ϩ/ eration of studies, which includes the use of transgenic calmodulin-dependent isozymes of cyclic nucleotide mouse technology, is beginning to reveal interesting yet phosphodiesterase and adenylate cyclase by competing sometimes subtle roles for this enzyme in the whole organ- for calmodulin in a Ca2ϩ-dependent fashion, and they ism (181, 254, 281, 320, 460, 477). speculated that its function may be regulatory (435, 436, It will not be the attempt of this review to provide an 445). Shortly thereafter, Klee et al. (204) coined the de- all-encompassing survey of calcineurin. In fact, several scriptive label “calcineurin” on the basis of its Ca2ϩ-bind- Downloaded from excellent review articles on calcineurin and other protein ing properties and localization to neuronal tissue (204), a serine/threonine phosphatases are available, some quite popularized name which is widely used to date and which comprehensive (60, 130, 203, 205, 207, 208, 316, 371). In we will use throughout this review. At that time, the true addition, numerous specialized articles focusing on par- function of calcineurin had yet to be revealed. It was not ticular aspects of either calcineurin structure or function until pioneering work in the early 1980s in Philip Cohen’s have been published. A list of these appears in Table 1 for lab, investigating cellular extracts capable of dephosphor- the benefit of the reader who would prefer to be directed ylating the ␣- and ␤-subunits of phosphorylase kinase, physrev.physiology.org to specific calcineurin-related topics. Rather, we focus on that a fraction represented as protein phosphatase 2B a comprehensive treatise of some of the recent develop- (PP2B) was demonstrated to be identical to Klee’s cal- ments of calcineurin since the last major review was cineurin (390, 391). published (371) (ca. 1990 to present). B. Calcineurin Properties II. A BRIEF HISTORY AND OVERVIEW OF CALCINEURIN Biochemical studies during the 1980s continued and on April 15, 2008 determined many of the physical properties listed in Table A. Calcineurin: The Early Years 2
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