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整联蛋白功能的特异性由α亚基决定。这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中可见，它们不仅具有 不同的胶原蛋白的不同的亲和力（由它们的细胞外结构域决定），而且还以关键依赖于它们的跨膜（TM）和胞质（CT）结构域的方式介导不同的信号。含有β-1整合素的TM和CT结构域的信号转导的分子机制知之甚少，因为大多数关于这些结构域的已发表工作是用高度可调节的α-s-β-3整合素进行的，并且主要集中在β-3亚基本身。我们最近发现，整合素α-1和α-2 TM和CT结构域有助于整合素α-1-β-1和α-2-β-1功能的非常不同的特异性。此外，已经鉴定了通过整合素α-1和α-2 CT尾调控特异性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的作用机制。特别是，我们将测试的假设，在TM或CT域的整合素α-1-β-1和α-2-β-1的特定残基是至关重要的赋予结构和功能的特异性。为了检验这一假设，我们将：目的1）确定单个整合的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异二聚体的结构。目的2）确定在细胞功能中控制整联蛋白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性的关键氨基酸。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。 公共卫生关系：我们预计，这项研究将产生新的见解的结构基础，其中TM和CT域的整合素α-1-β-1和α-2-β-1的功能。这一知识对于我们理解整合素如何从健康和疾病中的肾小球内的胶原蛋白中发出信号至关重要。