Cain, A Novel Physiologic Protein Inhibitor of Calcineurin*
- From the Departments of Neuroscience, §Pharmacology and Molecular Sciences, and ¶Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
Abstract
Calcineurin is a widely distributed protein phosphatase regulated by calcium and calmodulin. It mediates the immunosuppressive actions of drugs such as cyclosporin and FK506, and has been implicated in a number of calcium-sensitive pathways in the nervous system, including regulation of neurotransmitter release and modulation of long-term changes in synaptic plasticity. Calcineurin associates physiologically with other proteins, including calmodulin, FKBP12 (FK506-binding protein), the ryanodine receptor, and the inositol 1,4,5-trisphosphate receptor. We now report the identification, molecular cloning, and functional characterization of a novel protein, cain (calcineurininhibitor), that interacts with and inhibits calcineurin. The full-length cain cDNA predicts a 240-kDa protein with no significant homology to any known protein. Cain associates with calcineurin both in vitro and in vivo, leading to a non-competitive inhibition of calcineurin activity. The putative calcineurin-binding domain of cain, a 38-amino acid region defined by mutational analysis, is highly basic. Like calcineurin, cain has a prominent neuronal expression and a wide tissue distribution. Cain’s expression pattern in the brain closely resembles that of calcineurin, indicating a physiologic association between the two proteins.
Footnotes
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↵* This work was supported by United States Public Health Service Grant MH-18501 from the National Institute of Mental Health, Research Scientist Award DA-00074 (to S. H. S.) from NIDA, National Institutes of Health, and Training Grant GM-07309 (to M. M. L. and P. E. B.) from NIGMS, National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) .
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↵‡ Pew fellow.
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↵‖ To whom all correspondence should be addressed. Tel.: 410-955-3024; Fax: 410-955-3623.
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↵1 The abbreviations used are: CnA, 60-kDa catalytic subunit; CaB, 19-kDa calcium-binding regulatory subunit; NMDA, N-methyl-d-aspartate.
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- Received March 2, 1998.
- Revision received April 13, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
