Molecular Genetics of Cytoplasmic Dyein

细胞质染料的分子遗传学

基本信息

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
项目类别：
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

项目摘要

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）：动力蛋白是一类运动蛋白，涉及微管依赖性运动的许多方面。尤其是细胞质动力蛋白，负责各种形式的囊泡，大分子和有丝分裂运动，以及微管细胞骨架和定向细胞运动的组织。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各种亚细胞结构，代表了该领域的两个主要问题。该提案追求针对每个或这些问题的目标，该提案基于上一个项目期间的进度。 AIM I处理茎，这是从运动域延伸的15 nm长的投影，该投影负责微管结合。这个目标将确定原子分辨率下的茎的结构。它将进一步确定其推定的反平行线圈螺旋线D螺旋内的构象变化，负责微管结合和ATP水解的长距离变构耦合。 AIM II解决了涉及细胞质动力蛋白货物结合的机制。我们最近的研究揭示了ZW10蛋白复合物在将dynactin和Dynein与各种亚细胞结构联系起来的一般作用。我们将定义负责ZW10膜结合的机制；为了关注高尔基体，我们将确定ZW10相对于Rab6，Spectrin和与Dynein货物结合有关的其他因素的作用，以完全阐明高尔基货物结合途径的目的。 AIM III将涉及动力蛋白介导的病毒运动。我们将专注于腺病毒作为Dynein货物的结构简单致病形式。我们将扩展并完成我们的努力，以确定Dynein和腺病毒Capsid之间的相互作用伙伴。这些研究共同了解正常和异常细胞和发育生物学的许多方面具有重要意义。最终目标对于控制急性病毒感染以及基因输送载体和策略的设计具有特殊意义。