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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

基本信息

批准号：
9270816
负责人：
CHARLES R SANDERS
金额：
$ 0.1万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9270816
关键词：
Structure Function Analysis Integrins alpha1beta1

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.

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功能的特异性非常不同。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。