STRUCTURAL BASIS OF CA2+-CALMODULIN-CALCINEURIN SIGNALLING

CA2-钙调蛋白-钙调磷酸酶信号传导的结构基础

• 批准号: 8361729
• 负责人: Anjana Rao
• 金额: $ 0.18万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361729
• 关键词: Address; Blood Vessels; Calcineurin; Calcineurin Pathway; Calmodulin; Clinical; Cyclosporine; Cytokine Gene; Developmental Process; Funding; Genes; Genetic Transcription; Goals; Grant; Heart Valves; Hypertrophy; Immunosuppressive Agents; Individual; Injury; Kinetics; Myocardial; National Center for Research Resources; Pharmaceutical Preparations; Phosphoserine; Phosphothreonine; Principal Investigator; Proteins; Research; Research Infrastructure; Resources; Role; Signal Transduction; Source; T-Cell Activation; T-Lymphocyte; Tacrolimus; Translating; United States National Institutes of Health; Vascular System; base; cost; genetic regulatory protein; protein protein interaction; restenosis; structural biology; transcription factor

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 这个子项目的总体目标是获得详细的结构和动力学信息的信号在钙离子-钙调蛋白-钙调磷酸酶途径。 钙调神经磷酸酶（CN）通过细胞微区的Ca 2+信号局部激活或通过广泛的细胞质Ca 2+信号全局激活，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细胞中具有突出的作用，其中它调节转录因子NFAT，从而调节细胞因子基因和与T细胞活化相关的其他基因的转录。 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还涉及发育过程，包括心脏瓣膜和血管系统的正确形成，以及病理生理变化，包括心肌肥大和损伤后血管再狭窄。 该项目涉及 (1)如何通过识别单个CN底物来引导CN信号传导; (2)如何通过与靶向和调节蛋白的相互作用来引导CN信号传导; (3)引发和维持CN活化的构象变化;以及 (4)构象变化和蛋白质-蛋白质相互作用的动力学，将细胞质Ca信号转化为CN信号。