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绑定α和β亚基形成的跨膜受体。 β-1亚基结合了12个α亚基，这表明α-beta-1整联蛋白的功能特异性由α亚基确定。这在两个主要的胶原结合受体分别是整联蛋白alpha-1-beta-1和alpha-2-beta-1中可以看出，它们不仅对各种胶原蛋白具有不同的亲和力（由它们的细胞外域确定），而且还以批判性地依赖于跨内膜（TM）和细胞纤维（CT）的方式介导不同的信号。含有整合素的β-1的TM和CT结构域的分子机制知之甚少，因为大多数已发表在这些结构域上的已发表的工作都是用高度可调节的alpha-s-S-Beta-3整合蛋白进行的，并且主要集中在Beta-3亚基本身上。我们最近表明，整联蛋白alpha-1和alpha-2 TM和CT结构域有助于整联蛋白alpha-1-beta-1和alpha-2-beta-1函数的截然不同的特异性。此外，已经确定了整合素α-1和alpha-2 CT尾巴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联蛋白Alpha-1-Beta-1和Alpha-2-Beta-1的TM和CT域的机制，有助于其功能特异性。特别是，我们将检验以下假设：整联蛋白alpha-1-beta-1和alpha-2-beta-1的TM或CT结构域中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）确定单个积分alpha-1，alpha-2和beta-1 TM/CT域以及alpha-1-beta-1和alpha-1-beta-1和alpha-2-beta-1-beta-1 TM/CT异二聚体的结构。目标2）确定整联蛋白Alpha-1-Beta-1和Alpha-1-Beta-1和Alpha-2-Beta-1在细胞功能中控制α-1和α-2 TM域的特异性和功能的临界氨基酸。目标3）开发了TM/CD域在整合素alpha-1-beta-1和alpha-2-beta-1功能和特异性中的作用的模型。 公共卫生相关性：我们预计这项研究将产生对结构基础的新见解，在该结构基础上，整联蛋白Alpha-1-Beta-1和Alpha-2-Beta-1功能的TM和CT域。这种知识是我们对整合素在健康和疾病中胶原蛋白如何转导信号的理解至关重要的。