Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
基本信息
- 批准号:8002171
- 负责人:
- 金额:$ 38.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffinityAmino AcidsAreaBindingBiophysicsCell DeathCell physiologyCellsCellular biologyChronic Kidney FailureCollagenCollagen ReceptorsCollagen Type IVComplexCytoplasmic StructuresCytoplasmic TailDiseaseECM receptorEtiologyExtracellular DomainExtracellular MatrixGoalsHealthHomeostasisIndividualInduced MutationIntegrin alpha1Integrin beta3IntegrinsKidney GlomerulusKnowledgeLengthLigand BindingLigandsMammalian CellMediatingMesenchymalMethodsModelingMolecularMolecular BiologyMutagenesisNephronsParentsPathologyPlayProteinsPublishingRelative (related person)Renal glomerular diseaseResolutionRoleScanningSignal TransductionSpecificityStructureStructure-Activity RelationshipTestingTransmembrane DomainUnited StatesWorkbasecell typefollow-upglomerulosclerosisinsightintegrin alpha1beta1intermolecular interactionmembrane modelmesangial cellmutantnovelpublic health relevancereceptorreceptor bindingrole model
项目摘要
DESCRIPTION (provided by applicant): Integrins are transmembrane receptors formed by non-covalently bound alpha and beta subunits. The beta-1 subunit binds 12 alpha subunits, suggesting that specificity of function of alpha-beta-1 integrins are determined by the alpha subunits. This is seen in the two major collagen binding receptors, integrins alpha-1-beta-1 and alpha-2-beta-1, which not only have different affinities for various collagens (determined by their extracellular domains), but also mediate different signals in a manner that is critically dependent on their transmembrane (TM) and cytoplasmic (CT) domains. The molecular mechanisms whereby the TM and CT domains of beta-1 containing integrins transduce signals are poorly understood, as most published work on these domains was performed with the highly modulatable alpha-s-beta-3 integrins and focused primarily on the beta-3 subunit itself. We recently showed that integrin alpha-1 and alpha-2 TM and CT domains contribute to the very different specificities of integrin alpha-1-beta-1 and alpha-2-beta-1 function. Moreover, key amino acids that regulate specific signaling by the integrin alpha-1 and alpha-2 CT tails have been identified. Thus, the overall goal of this project is to identify the mechanisms whereby the TM and CT domains of integrins alpha-1-beta-1 and alpha-2-beta-1 contribute to their functional specificity. In particular, we will test the hypothesis that specific residues within the TM or CT domains of integrins alpha-1-beta-1 and alpha-2-beta-1 are critical for conferring structural and functional specificity. To test this hypothesis we will: Aim 1) Determine the structures of the individual integral alpha-1, alpha-2, and beta-1 TM/CT domains and of the alpha-1-beta-1 and alpha-2-beta-1 TM/CT heterodimers. Aim 2) Determine the critical amino acids that govern the specificity and functionality of the alpha-1 and alpha-2 TM domains of integrins alpha-1-beta-1 and alpha-2-beta-1 in cell function. Aim 3) Develop models for the roles of the TM/CD domains in integrin alpha-1-beta-1 and alpha-2-beta-1 function and specificity.
PUBLIC HEALTH RELEVANCE: We anticipate that this study will generate novel insights into the structural basis whereby the TM and CT domains of integrins alpha-1-beta-1 and alpha-2-beta-1 function. This knowledge is fundamental to our understanding of how integrins transduce signals from collagens within the glomerulus in both health and disease.
描述(由申请人提供):整合素是由非共价结合的α和β亚基形成的跨膜受体。β -1亚基结合12个α亚基,表明α - β -1整合素的功能特异性是由α亚基决定的。这在两种主要的胶原结合受体,整合素α -1- β -1和α -2- β -1中可见,它们不仅对各种胶原具有不同的亲和力(由它们的细胞外结构域决定),而且还以一种严重依赖于它们的跨膜(TM)和细胞质(CT)结构域的方式介导不同的信号。含有整合素的β -1的TM和CT结构域转导信号的分子机制尚不清楚,因为大多数发表的关于这些结构域的研究都是用高度可调节的α -s- β -3整合素进行的,主要集中在β -3亚基本身。我们最近发现,整合素α -1和α -2 TM和CT结构域对整合素α -1- β -1和α -2- β -1功能的特异性有很大的影响。此外,已经确定了通过整合素α -1和α -2 CT尾部调节特定信号传导的关键氨基酸。因此,本项目的总体目标是确定整合素α -1- β -1和α -2- β -1的TM和CT结构域有助于其功能特异性的机制。特别是,我们将验证整合素α -1- β -1和α -2- β -1的TM或CT结构域内的特定残基对于赋予结构和功能特异性至关重要的假设。为了验证这一假设,我们将:目标1)确定单个积分α -1、α -2和β -1 TM/CT结构域以及α -1- β -1和α -2- β -1 TM/CT异源二聚体的结构。目的2)确定控制整合素α -1- β -1和α -2- β -1的α -1和α -2 TM结构域在细胞功能中的特异性和功能的关键氨基酸。目的3)建立TM/CD结构域在整合素α -1- β -1和α -2- β -1功能和特异性中的作用模型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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CHARLES R SANDERS其他文献
CHARLES R SANDERS的其他文献
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Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
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Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
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$ 38.75万 - 项目类别:
Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
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$ 38.75万 - 项目类别:
Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2
整合素α1β1和α2β2的结构功能分析
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