Regulation of Microtubule Dynamics

 描述（由申请人提供）：动态微管（MT）的调节对于细胞分裂、细胞迁移、细胞极性、细胞器运动和核定位等细胞过程至关重要。了解MT调控的保守机制与人类生物学和疾病如癌症、神经元疾病和伤口愈合高度相关。在这项资助中，我们的目标是通过研究MT加末端跟踪蛋白（+TIPs）来阐明负责MT调控的基本保守机制。这些蛋白质包被MT+末端并控制这些聚合物的组装、稳定性和分解。一般来说，这些蛋白质如何共同调节MT在体内的动力学是一个紧迫的问题，在这个活跃的领域。我们研究MT调节使用在体内和体外的方法，使用裂殖酵母粟酒裂殖酵母作为一个易于处理的，简单的模型系统。XMAP 215/Alp 14家族的+TIP正在成为最重要的+TIP之一。这些微管蛋白结合蛋白作为MT聚合酶，将微管蛋白添加到生长的MT末端。我们的初步结果表明，它有额外的功能，在MT成核和拆卸。我们的具体目标是：1）明确Alp 14与γ微管蛋白复合物在MT成核中的作用机制; 2）确定Alp 14和驱动蛋白-8（kinesin-8）Klp 5/6如何调控MT的解聚; 3）阐明XMAP 215/Alp 14蛋白与微管蛋白相互作用调控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.