Structural investigation of focal adhesion formation and disassembly

粘着斑形成和分解的结构研究

• 批准号: 8461550
• 负责人: JIE J. ZHENG
• 金额: $ 32.09万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461550
• 关键词: Adaptor Signaling Protein; Address; Affect; Affinity; Area; Aspartate; Binding; C-terminal; Cell Adhesion Molecules; Chemicals; Complex; Coupled; Development; Dissociation; Equilibrium; Event; Focal Adhesion Kinase 1; Focal Adhesions; GIT1 gene; GTP-Binding Proteins; Goals; Integrin-mediated Cell Adhesion Pathway; Investigation; Knowledge; Lead; Leucine; Malignant Neoplasms; Mediating; Methods; Molecular; N-terminal; Nature; PTK2 gene; Phosphorylation; Phosphotransferases; Play; Protein Family; Protein Tyrosine Kinase; Proteins; Regulation; Resolution; Role; SH3 Domains; Scaffolding Protein; Signal Transduction; Structure; Therapeutic Agents; Work; cell motility; design; human BCAR1 protein; human disease; inhibitor/antagonist; leupaxin; paxillin; protein complex; protein protein interaction; protein tyrosine kinase PYK2

DESCRIPTION (provided by applicant): Cell migration is promoted by the alternating formation and disassembly of focal adhesions (FAs); our long-term goal is to understand the mechanisms that govern these dynamic events. In FA formation, multiple adhesion molecules are concentrated in a small area in which complex protein interactions are highly specific, although some of the binding affinities are relatively weak. Because of the relatively high protein concentration at the FA locus, binding affinity plays a critical role, and phosphorylation-mediated changes in binding affinity can completely alter the balance of interactions within the complex network. Therefore, to elucidate the mechanism that regulates the formation and disassembly of focal adhesions, we must understand in detail the structural and biophysical interactions within FAs and their binding partners and determine how phosphorylation affects these interactions; this is the focus of the project. Specifically, we will study paxillin family proteins and their biding partners in FAs. Paxillin and its related proteins are key players in FAs; as scaffold proteins, they use their N-terminal LD motifs to interact with other FA molecules. One major group of LD binding partners comprises the focal adhesion targeting (FAT) domain of FAK and the FAT-like domains of other FA proteins. Although the FAT-like domains have similar structures, their interactions with the LD motifs of paxillin family proteins differ in many ways. These differences offer an opportune starting point to dissect the dynamics of the complex interactions in FA formation and disassembly. This study will also aid in the design of inhibitors that target specifi binding events in FAs in order to mediate FA dynamics.

描述（由申请人提供）：细胞迁移是通过局灶性粘连（FA）的交替形成和分解来促进的;我们的长期目标是了解控制这些动态事件的机制。在FA形成中，多个粘附分子集中在一个小区域，其中复杂的蛋白质相互作用是高度特异性的，尽管一些结合亲和力相对较弱。因为相对高的蛋白质 在FA位点的浓度，结合亲和力起着关键作用，磷酸化介导的 结合亲和力的变化可以完全改变复杂网络内相互作用的平衡。因此，为了阐明调节粘着斑形成和分解的机制，我们必须详细了解FA及其结合伴侣之间的结构和生物物理相互作用，并确定磷酸化如何影响这些相互作用;这是该项目的重点。具体来说，我们将研究桩蛋白家族蛋白质和他们的biding合作伙伴在脂肪酸。桩蛋白及其相关蛋白是FA的关键参与者;作为支架蛋白，它们利用其N-末端LD基序与其他FA分子相互作用。LD结合配偶体的一个主要组包括FAK的粘着斑靶向（FAT）结构域和其它FA蛋白的FAT样结构域。虽然脂肪样结构域具有相似的结构，但它们与桩蛋白家族蛋白的LD基序的相互作用在许多方面不同。这些差异提供了一个合适的起点，解剖FA的形成和拆卸的复杂的相互作用的动力学。这项研究还将有助于设计抑制剂，靶向特异性结合事件的FA，以介导FA动力学。