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Mechanism of Microtubule Dynamics Regulation by Kinesins

驱动蛋白调节微管动力学的机制

基本信息

批准号：
10734209
负责人：
HERNANDO Jose SOSA
金额：
$ 57.62万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734209
关键词：
3-Dimensional ATP Hydrolysis Address Affect Antineoplastic Agents Binding Biological Assay Cell division Cell physiology Centrioles Cilia Classification Complex Coupling Cryoelectron Microscopy Cytokinesis Cytoskeletal Proteins Cytoskeleton Data Development Elements Family Family member Generations Grant Hydrolysis Kinesin Knowledge Length Malignant Neoplasms Microtubule Depolymerization Microtubule Polymerization Microtubules Mitosis Molecular Molecular Conformation Molecular Mechanisms of Action Molecular Structure Motor Movement Mutate Nucleotides Pharmaceutical Preparations Play Power stroke Proteins Regulation Reporting Resolution Role Structure Testing Tubular formation Tubulin Work cancer therapy cell motility comparative depolymerization dimer human disease member neurodevelopment optic trap optical traps prevent rational design therapeutic target transmission process tumor growth

项目摘要

Kinesins are eukaryotic cytoskeletal proteins best known for their motile activity, but they are also important regulators of microtubule dynamics, the ability of the microtubule polymer to grow or shrink. This project seeks to establish the molecular mechanisms and adaptations that allows different members of the kinesin superfamily to move along microtubules or to modulate microtubule dynamics. Regulation of microtubule dynamics by kinesins play important roles in a variety of cell processes such as mitosis, cytokinesis, neural development and the control of cilia and centriole length, but the mechanisms by which these kinesins stabilize or destabilize microtubules is still not fully clear. It is also not clear what conformational changes kinesins induce on the microtubule and whether these conformational changes are transmitted through the microtubule to allosterically modulate the binding of kinesin and other proteins along microtubules. To address these questions, we will perform cryo-electron microscopy structural and functional studies of motile and microtubule depolymerase kinesins, and their effect on microtubule structure. The proposal is divided into three aims: 1) Determine the allosteric effects of kinesin binding on microtubule structure and function. 2) Determine the mechanism of combined motile and microtubule depolymerization activities of Kinesin-8s. 3) Determine the origin of different functionalities among microtubule depolymerase kinesins.

驱动蛋白是真核细胞骨架蛋白，以其运动活性而闻名，但它们也是微管动力学的重要调节剂，微管聚合物生长的能力或心理医生该项目旨在建立分子机制和适应性，驱动蛋白超家族的不同成员沿沿着微管移动或调节微管动力学驱动蛋白对微管动力学的调节在细胞凋亡中起重要作用。多种细胞过程，如有丝分裂、胞质分裂、神经发育和纤毛的控制和中心粒长度，但这些驱动蛋白稳定或不稳定的机制微管仍然不完全清楚。驱动蛋白诱导的构象变化也不清楚以及这些构象变化是否通过微管蛋白的功能是变构地调节驱动蛋白和其他蛋白质沿沿着的结合。为了解决这些问题，我们将进行冷冻电子显微镜结构和功能运动和微管解聚酶驱动蛋白及其对微管作用的研究结构本研究的目的分为三个方面：1）确定驱动蛋白的变构效应结合微管结构和功能。2)确定联合运动的机制和微管解聚活性。3)确定不同的起源微管解聚酶驱动蛋白之间的功能。