STRUCTURAL BASIS OF CA2+-CALMODULIN-CALCINEURIN SIGNALLING

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这个子项目的总体目标是获得有关钙-钙调蛋白-钙调神经磷酸酶途径信号的详细结构和动力学信息。钙调神经磷酸酶(Calcineurin，CN)可被细胞微区内的钙信号局部激活，也可被广泛存在的细胞质内的钙信号激活，并通过使特定的磷酸丝氨酸或磷酸苏氨酸残基去磷酸化来控制其他细胞蛋白的活性。 CN在T细胞中具有显著的作用，它调节转录因子NFAT，从而调节细胞因子基因和其他与T细胞激活相关的基因的转录。CN的这种作用是临床免疫抑制药物环孢素A和他克莫司的靶点。CN还参与发育过程，包括心脏瓣膜和血管系统的正常形成，并参与病理生理变化，包括心肌肥大和损伤后血管再狭窄。 本项目致力于 (1)CN信号如何通过识别单个CN底物来定向； (2)CN信号如何通过与靶向蛋白和调节蛋白的相互作用而被定向； (3)启动和维持CN激活的构象变化； (4)将胞质钙信号转化为CN信号的构象变化和蛋白质-蛋白质相互作用的动力学。

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.