CRYSTAL STRUCTURE OF A COILED COIL DOMAIN OF HUMAN P160ROCK

人类 P160ROCK 的螺旋线圈域的晶体结构

• 批准号: 8169314
• 负责人: MICHAEL J ECK
• 金额: $ 4.69万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169314
• 关键词: Actins; Asthma; Binding; Cell Polarity; Cell physiology; Coiled-Coil Domain; Computer Retrieval of Information on Scientific Projects Database; Cytokinesis; Eukaryota; Filament; Focal Adhesions; Funding; Grant; Homologous Gene; Human; Hypertension; Institution; Light; Mediating; Microfilaments; Morphogenesis; Neoplasm Metastasis; Neurites; Pathway interactions; Play; Process; Proteins; ROCK1 gene; Research; Research Personnel; Resources; Rho-associated kinase; Role; Signal Transduction; Smooth Muscle; Source; Stress Fibers; Structure; Tumor Cell Invasion; United States National Institutes of Health; Work; Yeasts; cell motility; drug development; rho; yeast protein

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Formins are multidomain proteins that participate in a wide range of cytoskeletal processes. They are required for cell polarity, cell migration, cytokinesis, and morphogenesis in all eukaryotes. The defining feature of formin proteins is the Formin Homology 2 (FH2) domain, which directly nucleates actin filaments and remains processively associated with the barbed end of the filament as it grows. To better understand how formins work in specific cellular contexts, we are studying a genetically and biochemically well-validated formin partner protein, the yeast protein Bud6. Bud6 is a key binding partner and regulator of the formin Bni1 in yeast. We have recently determined the structure of a core domain in Bud6 that binds to Bni1 (unpublished). Bud6 has no known human homologs. However, re-examination of a weak similarity in primary sequence between this region of Bud6 and the mammalian protein ROCK1, in light of the structure, suggests that the sequence similarity is reflective of a shared structural and perhaps functional feature in these two proteins. ROCK (Rho-associated kinase) is an effector of Rho-dependent signaling to mediate stress fibers and focal adhesion formation. It is also involved in many other cellular processes including smooth muscle contraction, cell migration, and neurite outgrowth. Abnormal activation of the Rho-ROCK pathway plays role in tumor invasion and metastasis, hypertension, and bronchial asthma. A structural and functional parallel between the actin binding domains of Bud6 and human ROCK1 if proven correct will be a breakthrough finding. Their similar structures can be a target for drug development.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 福尔明是参与多种细胞骨架过程的多域蛋白。 它们是所有真核生物的细胞极性、细胞迁移、胞质分裂和形态发生所必需的。 福尔明蛋白的定义特征是福尔明同源性 2 (FH2) 结构域，它直接使肌动蛋白丝成核，并在肌动蛋白丝生长时与丝的带刺末端持续相关。 为了更好地了解福尔明如何在特定细胞环境中发挥作用，我们正在研究一种经过遗传和生化验证的福尔明伴侣蛋白，即酵母蛋白 Bud6。 Bud6 是酵母中 Formin Bni1 的关键结合伴侣和调节因子。 我们最近确定了 Bud6 中与 Bni1 结合的核心结构域的结构（未发表）。 Bud6 没有已知的人类同源物。 然而，根据结构重新检查 Bud6 的该区域和哺乳动物蛋白 ROCK1 之间一级序列的弱相似性表明，序列相似性反映了这两种蛋白共有的结构和功能特征。 ROCK（Rho 相关激酶）是 Rho 依赖性信号传导的效应器，可介导应力纤维和粘着斑形成。 它还参与许多其他细胞过程，包括平滑肌收缩、细胞迁移和神经突生长。 Rho-ROCK 通路的异常激活在肿瘤侵袭和转移、高血压和支气管哮喘中发挥作用。 如果被证明正确的话，Bud6 和人类 ROCK1 的肌动蛋白结合域之间的结构和功能相似将是一个突破性的发现。 它们相似的结构可以成为药物开发的目标。