Structural Basis of Kinesin Motor Movement

描述（由申请人提供）：驱动蛋白包括一百多种不同的蛋白质超家族，所有蛋白质都含有高度保守的球状催化结构域，具有atp酶和微管结合活性。尽管它们的运动域具有高度的同源性和相似的三维结构，但不同的运动蛋白之间存在相当大的功能差异。大多数运动蛋白，如运动蛋白1和运动蛋白5，沿着微管运动并产生力（助行器），但一些运动蛋白，如运动蛋白13s，积极地解聚微管（解聚合酶）。目前尚不清楚如何非常相似的催化结构域（序列和3D结构）存在于整个激酶蛋白超家族中，可以执行这两种截然不同的功能。为了解决这一问题，本项目将应用几种生物物理和细胞生物学技术来研究kinesin13s和kinesin5s的结构和功能特征。我们将解决以下问题：1)kinesin13马达结构域稳定微管蛋白曲率的结构基础是什么？2)最近描述的微管环复合物（kinesin13家族独有的）的生理作用是什么？3)微管晶格上kinesin13一维扩散（ODD）的机理是什么？4) kinesin5的易位机制是否与其他kinesin1不同？所提出的研究将揭示两种驱动蛋白类型中不同的蛋白质结构域和二级结构元件如何导致其不同的功能。kinesin5和kinesin13都是抗肿瘤化疗的潜在靶点。因此，提出的研究可能为开发更有效的癌症治疗方法提供新的见解。公共卫生相关性：本项目旨在阐明两种不同的运动蛋白，kinesin5s和kinesin13s的作用机制。这些运动蛋白在细胞分裂过程中起重要作用，是抗癌药物的潜在靶点。了解这些蛋白质的工作原理可能有助于找到更好的癌症治疗方法。

DESCRIPTION (provided by applicant): Kinesins comprise a diverse superfamily of over one hundred different proteins, all containing a highly conserved globular catalytic domain with ATPase and microtubule binding activities. Despite the high degree of homology and similar three-dimensional structure of their motor domains, there is considerable functional variability among different kinesins. Most kinesins, such as kinesin1s and kinesin5s, move and generate force along microtubules (walkers), but some, such as kinesin13s, actively depolymerize microtubules (depolymerases). It is not clear how very similar catalytic domains (sequence and 3D structure) present throughout the kinesin superfamily can perform these two very different functions. To address this issue in this project we will apply several biophysical and cell biology techniques to investigate structural and functional characteristic of kinesin13s and kinesin5s. We will address the following questions: 1) What is the structural basis of the stabilization of tubulin curvature by the kinesin13 motor domain? 2) What is the physiological role of the recently described microtubule-ring complexes, unique to the kinesin13 family? 3) What is the mechanism of kinesin13 one-dimensional diffusion (ODD) on the microtubule lattice? 4) Is the translocation mechanism of kinesin5 different from other kinesin walkers, such as kinesin1? The proposed studies will reveal how different protein domains and secondary structure elements in the two kinesin types lead to their different functionality. Both kinesin5 and kinesin13 are potential targets for anti-tumor chemotherapy. Thus, the proposed studies may provide new insights to develop more effective therapies against cancer. PUBLIC HEALTH RELEVANCE: This project seeks to elucidate the mechanism of action of two different motor proteins, the kinesin5s and the kinesin13s. These kinesins are important during cell division and are potential targets for anti-cancer drugs. Understanding how these proteins work may help finding better treatments for cancer.