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STRUCTURAL INVESTIGATION OF FOCAL ADHESION MOLECULES

焦点粘附分子的结构研究

基本信息

批准号：
7175342
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
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7175342
关键词：
Actins Affinity Amino Acids Apoptosis Area Aspartate Binding Binding Sites Biochemical C-terminal Cell Adhesion Molecules Cell Proliferation Cell Shape Cell Survival Chemicals Complex Cytoskeleton Development Extracellular Matrix Extracellular Matrix Proteins Family Focal Adhesion Kinase 1 Focal Adhesions Integrin Binding Integrin-mediated Cell Adhesion Pathway Integrins Investigation Knowledge Lead Ligands Link Malignant Neoplasms Mediating Methods Molecular Molecular Structure Mutation N-terminal NMR Spectroscopy Nature Output Pathway interactions Personal Satisfaction Phosphotransferases Principal Investigator Protein NMR Spectroscopy Protein Tyrosine Kinase Proteins Research Personnel Resolution Role Signal Pathway Signal Transduction Signaling Protein Solutions Structure Surface System Talin Testing Therapeutic Agents base cell motility design human disease inhibitor/antagonist migration paxillin programs protein protein interaction receptor

项目摘要

DESCRIPTION (provided by applicant): By linking extracellular matrix (ECM) proteins to the actin cytoskeleton, integrin proteins regulate cell proliferation, migration, and survival. A key player in integrin signaling is focal adhesion kinase (FAK). Activation and localization of FAK to focal adhesions results from the binding of integrins to ECM proteins. Activated FAK relays signal from integrins to downstream components of different pathways. However, inappropriate activation of FAK and inappropriate FAK-regulated signaling has been implicated in cancer and other human diseases. Therefore, the long-term objective is to investigate structures and molecular mechanisms underlying regulatory and targeting interactions of FAK-regulated signaling pathways. This objective will be achieved through the use of biophysical methods. Studies showed that FAK's C-terminal focal adhesion targeting (FAT) domain is necessary and sufficient for the targeting of FAK to focal adhesions, a crucial step in FAK signaling. On the basis of preliminary findings described in this application, it is hypothesized that the FAT domain regulates FAK activation by interacting with FAK's N-terminal FERM domain. Previously, the principal investigator determined the solution structure of the FAT domain by NMR spectroscopy. In proposed studies, this method will be used to determine the chemical nature of interactions between the FAT domain and its binding partners: paxillin, talin, and FAK's FERM domain. Furthermore, the complex molecular interplay among FAK, paxillin, and talin will be evaluated. These studies will provide structural and functional information at the atomic level about the FAT domain and its associated proteins. Also, ligands designed to serve as FAT domain inhibitors, will be tested to determine whether they provide a lead in developing therapies that interfere specifically with abnormal FAK-mediated signaling that contributes to cancer.

描述（由申请人提供）：通过将细胞外基质（ECM）蛋白连接到肌动蛋白细胞骨架，整联蛋白调节细胞增殖、迁移和存活。整合素信号传导中的关键参与者是粘着斑激酶（FAK）。粘着斑激酶的活化和定位是由整合素与ECM蛋白的结合引起的。活化的FAK将信号从整合素传递到不同途径的下游组分。然而，FAK的不适当激活和不适当的FAK调节信号转导与癌症和其他人类疾病有关。因此，长期目标是研究FAK调节的信号通路的结构和分子机制。这一目标将通过使用生物物理方法来实现。研究表明，FAK的C末端粘着斑靶向（FAT）结构域是FAK靶向粘着斑的必要和充分条件，这是FAK信号传导的关键步骤。基于本申请中描述的初步发现，假设FAT结构域通过与FAK的N-末端FERM结构域相互作用来调节FAK活化。此前，主要研究者通过NMR光谱确定了FAT结构域的溶液结构。在拟议的研究中，该方法将用于确定FAT结构域与其结合伙伴（桩蛋白、talin和FAK的FERM结构域）之间相互作用的化学性质。此外，FAK，桩蛋白，和talin之间的复杂的分子相互作用将进行评估。这些研究将在原子水平上提供有关FAT结构域及其相关蛋白质的结构和功能信息。此外，将对设计用作FAT结构域抑制剂的配体进行测试，以确定它们是否在开发特异性干扰导致癌症的异常FAK介导的信号传导的疗法中提供先导。