Structure Function Analysis of Integrins alpha1beta1 and alpha2beta2

整合素α1β1和α2β2的结构功能分析

• 批准号: 8002171
• 负责人: CHARLES R SANDERS
• 金额: $ 38.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8002171
• 关键词: 3-Dimensional; Affinity; Amino Acids; Area; Binding; Biophysics; Cell Death; Cell physiology; Cells; Cellular biology; Chronic Kidney Failure; Collagen; Collagen Receptors; Collagen Type IV; Complex; Cytoplasmic Structures; Cytoplasmic Tail; Disease; ECM receptor; Etiology; Extracellular Domain; Extracellular Matrix; Goals; Health; Homeostasis; Individual; Induced Mutation; Integrin alpha1; Integrin beta3; Integrins; Kidney Glomerulus; Knowledge; Length; Ligand Binding; Ligands; Mammalian Cell; Mediating; Mesenchymal; Methods; Modeling; Molecular; Molecular Biology; Mutagenesis; Nephrons; Parents; Pathology; Play; Proteins; Publishing; Relative (related person); Renal glomerular disease; Resolution; Role; Scanning; Signal Transduction; Specificity; Structure; Structure-Activity Relationship; Testing; Transmembrane Domain; United States; Work; base; cell type; follow-up; glomerulosclerosis; insight; integrin alpha1beta1; intermolecular interaction; membrane model; mesangial cell; mutant; novel; public health relevance; receptor; receptor binding; role model

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）：整联蛋白是由非共价结合的α和β亚基形成的跨膜受体。 beta-1 亚基结合 12 个 alpha 亚基，表明 alpha-beta-1 整联蛋白功能的特异性是由 alpha 亚基决定的。这可以在两种主要的胶原蛋白结合受体整合素 α-1-β-1 和 α-2-β-1 中看到，它们不仅对各种胶原蛋白具有不同的亲和力（由其细胞外结构域决定），而且还介导不同的信号以一种严重依赖于其跨膜（TM）和细胞质（CT）结构域的方式。含有整合素的 β1 的 TM 和 CT 结构域转导信号的分子机制尚不清楚，因为大多数已发表的关于这些结构域的工作都是使用高度可调节的 α-s-β-3 整合素进行的，并且主要集中于 β-3子单元本身。我们最近表明，整合素 α-1 和 α-2 TM 和 CT 结构域导致整合素 α-1-β-1 和 α-2-β-1 功能的非常不同的特异性。此外，还鉴定了通过整合素 α-1 和 α-2 CT 尾调节特定信号传导的关键氨基酸。因此，该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 结构域对其功能特异性做出贡献的机制。特别是，我们将测试以下假设：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。为了检验这一假设，我们将： 目标 1) 确定各个积分 alpha-1、alpha-2 和 beta-1 TM/CT 域以及 alpha-1-beta-1 和 alpha-2-beta- 的结构。 1 TM/CT 异二聚体。目标 2) 确定控制细胞功能中整合素 α-1-β-1 和 α-2-β-1 的 α-1 和 α-2 TM 结构域的特异性和功能的关键氨基酸。目标 3) 开发 TM/CD 结构域在整合素 alpha-1-beta-1 和 alpha-2-beta-1 功能和特异性中的作用模型。 公共健康相关性：我们预计这项研究将对整合素 α-1-β-1 和 α-2-β-1 的 TM 和 CT 结构域发挥功能的结构基础产生新的见解。这些知识对于我们了解整合素如何在健康和疾病中转导肾小球内胶原蛋白的信号至关重要。