This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of this subproject is to obtain detailed structural and kinetic information on signalling in the Ca2+-calmodulin-calcineurin pathway. Calcineurin (CN) is activated either locally by Ca2+ signals in cellular microdomains or globally by widespread cytoplasmic Ca2+ signals, and controls the activity of other cellular proteins by dephosphorylating specific phosphoserine or phosphothreonine residues. CN has a prominent role in T cells, where it regulates the transcription factor NFAT and thereby the transcription of cytokine genes and other genes associated with T cell activation. This role of CN is the target of the clinical immunosuppressive drugs cyclosporin A and tacrolimus. CN is also implicated in developmental processes, including the proper formation of cardiac valves and the vascular system, and in pathophysiological changes, including myocardial hypertrophy and vascular restenosis after injury. This project addresses (1) how CN signalling is directed through recognition of individual CN substrates; (2) how CN signalling is directed through interaction with targeting and regulatory proteins; (3) the conformational changes that initiate and sustain CN activation;and (4) the kinetics of the conformational changes and protein-protein interactions that translate cytoplasmic Ca signals into CN signalling.
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