Microtubule Mechanics at the Nanoscale

描述（由申请人提供）：微管是在建立和维持细胞结构中起关键作用的聚合物。微管是诸如长春花生物碱和紫杉醇（紫杉醇）等重要抗癌药物的靶标，并且被认为在阿尔茨海默氏症等神经退行性疾病中发挥作用。微管是蛋白质微管蛋白的动态聚合物，是一种GTP酶，GTP水解的能量驱动动态不稳定性，微管自发地在聚合和快速解聚之间切换。这种行为是由细胞调节的，以实现细胞骨架的快速重组。为了更好地理解动态不稳定性，我们开发了以纳米尺度分辨率跟踪微管聚合的方法，从而揭示了传统方法无法解决的基本行为。这项工作导致了对动态不稳定性的分子力学的基本重新评估，并为药物和微管相关蛋白调节微管动力学的机制提供了重要的见解。本研究将纳米分辨率微管动力学研究与分子建模相结合，了解紫杉醇在临床相关剂量下的详细作用，以及微管调节蛋白tau在阿尔茨海默病和其他神经退行性疾病中发挥重要作用。

DESCRIPTION (provided by applicant): Microtubules are polymers that serve critical roles in establishing and maintaining cellular architecture. Microtubules are the target of important anticancer drugs such as the vinca alkaloids and taxol (paclitaxel), and are thought to play a role in neurodegenerative diseases such as Alzheimer's. Microtubules are dynamic polymers of the protein tubulin, a GTPase, and the energy of GTP hydrolysis drives dynamic instability whereby microtubules spontaneously switch between periods of polymerization and rapid depolymerization. This behavior is regulated by cells to achieve rapid restructuring of the cytoskeleton. To better understand dynamic instability we have developed methods to track microtubule polymerization with nanometer scale resolution, thereby revealing fundamental behaviors that were not resolved by traditional approaches. This work has led to a fundamental reassessment of the molecular mechanics underlying dynamic instability, and provides important insight into the mechanisms by which drugs and microtubule associated proteins can regulate microtubule dynamics. Here we combine nanometer resolution studies of microtubule dynamics with molecular modeling to understand the detailed actions of taxol at clinically relevant doses, and the microtubule regulating protein tau, which plays an important role in Alzheimer's and other neurodegenerative diseases.