Structural investigation of focal adhesion formation and disassembly

粘着斑形成和分解的结构研究

• 批准号: 8270832
• 负责人: JIE J. ZHENG
• 金额: $ 33.25万
• 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/8270832
• 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. PUBLIC HEALTH RELEVANCE: Cell migration is promoted by the alternating formation and disassembly of focal adhesions; our long-term goal is to understand the mechanisms that govern these dynamic events. Inappropriate regulations of focal adhesion dynamics have been implicated in cancer and other human diseases. Therefore, the knowledge obtained from the studies in the current project will not only help to explain the fundamental chemical nature of the complex molecular interplay in focal adhesions but may also lead to the development of therapeutic agents that target pathogenic abnormalities in FA signaling.

描述（由申请人提供）：粘着斑（FA）的交替形成和分解促进细胞迁移；我们的长期目标是了解控制这些动态事件的机制。在 FA 形成过程中，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具有高度特异性，尽管一些结合亲和力相对较弱。因为蛋白质含量相对较高 FA位点的浓度、结合亲和力起着关键作用，并且磷酸化介导 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及其结合伙伴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及其在 FA 中的结合伙伴。 Paxillin 及其相关蛋白是 FA 中的关键角色；作为支架蛋白，它们利用 N 端 LD 基序与其他 FA 分子相互作用。 LD 结合配偶体的一大类包括 FAK 的粘着斑靶向 (FAT) 结构域和其他 FA 蛋白的 FAT 样结构域。尽管 FAT 样结构域具有相似的结构，但它们与桩蛋白家族蛋白 LD 基序的相互作用在许多方面有所不同。这些差异为剖析 FA 形成和分解中复杂相互作用的动态提供了一个合适的起点。这项研究还将有助于设计针对 FA 中特定结合事件的抑制剂，以介导 FA 动力学。 公共健康相关性：粘着斑的交替形成和分解促进细胞迁移；我们的长期目标是了解控制这些动态事件的机制。粘着斑动力学的不当调节与癌症和其他人类疾病有关。因此，从当前项目的研究中获得的知识不仅有助于解释该物质的基本化学性质 粘着斑中复杂的分子相互作用，但也可能导致针对 FA 信号传导致病异常的治疗药物的开发。