Molecular Genetics of Cytoplasmic Dyein

细胞质染料的分子遗传学

• 批准号: 7931548
• 负责人: Richard Bert Vallee
• 金额: $ 9.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931548
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Abnormal Cell; Acute; Address; Adenoviruses; Binding; Binding Sites; Biochemical; Capsid; Capsid Proteins; Cell Cycle; Cell Nucleus; Circular Dichroism Spectroscopy; Complex; Coupled; Coupling; Cytoskeleton; Developmental Biology; Developmental Cell Biology; Disulfides; Dynein ATPase; Early identification; Gene Delivery; Gene Transduction Agent; Goals; Golgi Apparatus; Grant; Hereditary Disease; Infection; Interphase; Investigation; Kinetochores; Link; Mediating; Membrane; Microtubules; Mitotic; Modeling; Molecular; Molecular Genetics; Motor; Movement; Nervous system structure; Organelles; Pathway interactions; Physiological; Process; Production; Proteins; Recombinants; Recruitment Activity; Regulation; Relative (related person); Resolution; Role; Series; Site; Specificity; Spectrin; Structure; Subcellular structure; Therapeutic; Therapeutic Intervention; Virus; Virus Diseases; Work; X-Ray Crystallography; base; cell cortex; cell motility; crosslink; design; dynactin; insight; latent infection; protein complex; structural biology; vector

DESCRIPTION (provided by applicant): The dyneins are a class of motor protein involved in many of aspects of microtubule-dependent movement. Cytoplasmic dynein, in particular, is responsible for diverse forms of vesicular, macromolecular, and mitotic movement, as well as organization of the microtubule cytoskeleton and directed cell movement. How the dyneins function to produce force, and how cytoplasmic dynein is selectively targeted to a diversity of subcellular structures represent two of the major outstanding issues in the field. This proposal pursues Aims directed at each or these issues based on progress during the preceding project period. Aim I deals with the stalk, a 15 nm long projection extending from the motor domain, which is responsible for microtubule binding. This Aim will determine the structure of the stalk at atomic resolution; it will further identify conformational changes within its putative antiparallel coiled-coil D-helix responsible for long-range allosteric coupling of microtubule binding and ATP hydrolysis. Aim II addresses mechanisms involved in cytoplasmic dynein cargo binding. Our recent studies have revealed a general role for the ZW10 protein complex in linking dynactin and dynein to diverse subcellular structures. We will define the mechanism responsible for ZW10 membrane binding; focusing on the Golgi apparatus, we will determine the role of ZW10 relative to Rab6, spectrin, and other factors implicated in dynein cargo binding, with the goal of a complete elucidation of the Golgi cargo binding pathway. Aim III will involve dynein-mediated virus motility. We will focus on adenovirus as a structurally simple pathogenic form of dynein cargo. We will extend and complete our efforts to identify the interacting partners between dynein and the adenovirus capsid. Together these studies have important implications for understanding many aspects of normal and abnormal cell and developmental biology. The final aim has particular significance for the control of acute viral infection and the design of gene delivery vectors and strategies.

描述（由申请人提供）：动力蛋白是一类参与微管依赖性运动的许多方面的运动蛋白。细胞质动力蛋白，特别是，是负责不同形式的囊泡，大分子和有丝分裂运动，以及组织的微管细胞骨架和定向细胞运动。动力蛋白如何产生力，以及细胞质动力蛋白如何选择性地靶向多种亚细胞结构，是该领域两个主要的突出问题。本提案根据上一个项目期间的进展情况，力求实现针对每一个或这些问题的目标。目的I涉及柄，一个15 nm长的突起从运动域延伸，这是负责微管结合。该目的将在原子分辨率下确定茎的结构;它将进一步确定其假定的反平行卷曲螺旋D-螺旋内的构象变化，该D-螺旋负责微管结合和ATP水解的远程变构偶联。目的二解决机制参与细胞质动力蛋白货物结合。我们最近的研究揭示了ZW 10蛋白复合物在连接动力蛋白和动力蛋白到不同的亚细胞结构中的一般作用。我们将定义负责ZW 10膜结合的机制;专注于高尔基体，我们将确定ZW 10相对于Rab 6，血影蛋白和其他参与动力蛋白货物结合的因素的作用，目标是完整阐明高尔基体货物结合途径。目的III将涉及动力蛋白介导的病毒运动。我们将重点放在腺病毒作为一种结构简单的致病形式的动力蛋白货物。我们将扩大和完成我们的努力，以确定动力蛋白和腺病毒衣壳之间的相互作用的合作伙伴。这些研究对于理解正常和异常细胞以及发育生物学的许多方面具有重要意义。其最终目的对于控制急性病毒感染和设计基因递送载体和策略具有特别重要的意义。