Mechanism of Microtubule Dynamics Regulation by Kinesins

驱动蛋白调节微管动力学的机制

• 批准号: 10333223
• 负责人: HERNANDO Jose SOSA
• 金额: $ 44.26万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10333223
• 关键词: ATP phosphohydrolase; Address; Affect; Antineoplastic Agents; Binding; Biochemical; Biological Assay; Cell division; Cell physiology; Centrioles; Chemicals; Cilia; Clinical; Complex; Coupled; Cryo-electron tomography; Cryoelectron Microscopy; Cytokinesis; Cytoskeletal Proteins; Cytoskeleton; Development; Docking; Electron Microscopy; Family; Generations; Goals; Kinesin; Kinesis; Lateral; Length; Malignant Neoplasms; Mechanics; Microtubule Depolymerization; Microtubule Polymerization; Microtubule Stabilization; Microtubules; Mitosis; Modeling; Molecular; Molecular Structure; Motor; Movement; Mutagenesis; Neck; Nucleotides; Pharmaceutical Preparations; Play; Polymers; Positioning Attribute; Principal Investigator; Process; Proteins; Regulation; Reporting; Research; Resolution; Role; Structure; Testing; Tubulin; Work; base; cancer therapy; cell motility; comparative; depolymerization; experimental study; in vitro Assay; member; neurodevelopment; neuroregulation; novel; particle; predictive modeling; programs; rational design; reconstruction; small molecule; therapeutic target; tumor growth

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 mechanism of microtubule dynamics regulation by members of the kinesin superfamily. Regulation of microtubule dynamics by these kinesins play important roles in a variety of cell processes such as mitosis, cytokinesis, neural development and control of cilia and centriole length, but the mechanisms by which these kinesins stabilize or destabilize microtubules is still not clear. It is not known how different kinesin may be adapted for seemingly different functionalities or whether they share common mechanisms. To address this issue we propose to conduct comparative structural and functional analysis of several kinesins with distinct functionalities: the microtubule depolymerase KLP10A (kinesin-13), the motile and microtubule stabilizers KIF14 (kinesin-3) and EG5 (kinesin- 5) and the archetypical motile kinesin KIF5B (kinesin-1). The proposal is divided in four aims. The first two aims test the hypothesis based on our recent work that the same ATPase related confomational changes occurring in the motor domain of kinesin-1s are adapted in kinesin-13s to depolymerize microtubules. The second aim investigates the mechanism by which EG5 promotes microtubule polymerization and inhibits depolymerization. The fourth aim uses cryo- em structural analysis to guide the development and optimization of KIF14 specific drugs for research and potentially clinical use.

驱动蛋白是真核细胞骨架蛋白，以其运动活性而闻名，但它们是 也是微管动力学的重要调节剂，微管聚合物生长的能力 或者心理医生本计画旨在建立微管动力学的分子机制 由驱动蛋白超家族成员调节。微管动力学的调节 驱动蛋白在多种细胞过程如有丝分裂、胞质分裂、神经细胞分裂和细胞分裂中起重要作用。 纤毛和中心粒长度的发展和控制，但这些机制， 驱动蛋白稳定或不稳定微管仍不清楚。不知道有多不同 驱动蛋白可能适用于表面上不同的功能，或者它们是否具有共同的 机制等为了解决这个问题，我们建议进行比较结构和 几种具有不同功能的驱动蛋白的功能分析：微管解聚酶 KLP 10A（驱动蛋白-13）、运动和微管稳定剂KIF 14（驱动蛋白-3）和EG 5（驱动蛋白-13）， 5)和原型运动驱动蛋白KIF 5 B（kinesin-1）。该提案分为四个目标。 前两个目的是基于我们最近的工作来检验假设，即相同的ATP酶相关于 发生在驱动蛋白-1s运动域的构象变化在驱动蛋白-13s中得到适应 去激活微管第二个目的是研究EG 5 促进微管聚合并抑制解聚。第四个目标是使用低温- em结构分析指导KIF 14特异性药物的开发和优化， 研究和潜在的临床应用。