Regulation of Microtubule Dynamics

 描述(由申请人提供)：动态微管(MTS)的调节对细胞过程至关重要，如细胞分裂、细胞迁移、细胞极性、细胞器运动和核定位。了解MT调节的保守机制与人类生物学以及癌症、神经性疾病和伤口愈合等疾病高度相关。在这项资助中，我们旨在通过研究MT+末端跟踪蛋白(+TIPS)来阐明负责MT调节的基本保守机制。这些蛋白质覆盖在MT Plus末端，控制这些聚合物的组装、稳定性和拆卸。总的来说，这些蛋白质如何共同作用来调节体内的MT动态是这一活跃领域中一个紧迫的问题。我们使用体内和体外的方法研究MT的调节，使用裂解酵母作为一个易于处理的简单的模型系统。XMAP215/Alp14家族的+TIPS正在成为最重要的+TIPS之一。这些微管蛋白结合蛋白作为MT聚合酶发挥作用，将微管蛋白添加到生长的MT的末端。我们的初步结果表明，它在MT成核和解体过程中具有额外的功能。我们的具体目标是：1)确定Alp14如何与Gamma微管蛋白复合体一起作用于MT成核；2)确定Alp14和Kinesin-8 Klp5/6如何调节MT的分解；3)阐明XMAP215/Alp14蛋白如何与微管蛋白相互作用来调节MT动力学的分子机制。

 DESCRIPTION (provided by applicant): Regulation of dynamic microtubules (MTs) is critical for cellular processes such as cell division, cell migration, cell polarity, organelle movements and nuclear positioning. Understanding conserved mechanisms of MT regulation are highly relevant to human biology and diseases such as cancer, neuronal diseases and wound healing. In this grant, we aim to elucidate fundamental conserved mechanisms responsible for MT regulation by studying MT plus end tracking proteins (+TIPs). These proteins coat the MT plus end and control the assembly, stability and disassembly of these polymers. In general, how these proteins work collectively to regulate MT dynamics in vivo is a pressing question in this active field. We study MT regulation using in vivo and in vitro approaches, using the fission yeast Schizosaccharomyces pombe as a tractable, simple model system. The XMAP215/Alp14 family of +TIPs is emerging as one of the most important of the +TIPs. These tubulin-binding proteins function as MT polymerases that add tubulin onto the ends of growing MT. Our preliminary results suggest that it has additional functions in MT nucleation and disassembly. Our specific aims are: 1) To define how Alp14 works with gamma tubulin complex for MT nucleation; 2) To determine how Alp14 and the kinesin-8 Klp5/6 regulate the disassembly of MTs; 3) To elucidate the molecular mechanisms of how XMAP215/Alp14 proteins interact with tubulin to regulate MT dynamics.