Structure and Interactions of Tubulin

微管蛋白在所有真核细胞的生命中起着至关重要的作用。微管主要由微管蛋白组成，参与细胞器的运动、细胞分裂过程中染色体的分离、细胞形状的维持以及其他关键的细胞活动。微管在特定时间的组装和拆卸是细胞周期的重要步骤。这些过程受到严密的调控，干扰调控机制可导致细胞死亡。这些特性使微管蛋白既成为生物物理研究的迷人样本，又成为抗癌药物的有用靶点。为了充分了解细胞的生命，了解微管蛋白分子如何相互作用以及与大量其他蛋白质和配体在这些活动中的相互作用是很重要的，作为在这个方向上的第一步，我们已经通过电子晶体学确定了微管蛋白的结构。在提出的工作中，我们将扩展我们对结构的理解，并更多地了解赋予微管蛋白独特性质的过程。我们将研究微管蛋白与稳定微管的药物的相互作用，以及与一些在微管上移动并调节微管细胞骨架的蛋白质的相互作用。通过基因操作，我们将研究赋予微管特定亚稳特性的因素。这项工作将导致对微管动力学功能机制的合理理解，并可能揭示微管稳定的潜在机制，最终允许开发新的，更有效的靶向微管蛋白的药物。

The protein tubulin plays a vital role in the life of all eukaryotic cells. Microtubules, made mostly of tubulin, are involved in organelle movement, separation of chromosomes during cell division, maintenance of cell shape and other critical cellular activities. The assembly and disassembly of microtubules at particular times are essential steps in the cell cycle. These processes are closely regulated, and interference with the regulatory mechanisms can lead to cell death. These properties have made tubulin both a fascinating specimen for biophysical studies and a useful target for anti-cancer drugs. It is important to understand how tubulin molecules interact with each other as well as with large number of other proteins and ligands in these activities in order to have a full understanding of the life of the cell, and as a first step in this direction we have determined the structure of tubulin by electron crystallography. In the proposed work we will extend our understanding of the structure and learn more about the processes that give tubulin its unique properties. We will study the interaction of tubulin with drugs that stabilize microtubules and the interactions with some of the proteins that move on microtubule and that regulate the microtubule cytoskeleton. Through genetic manipulation, we will investigate factors that give microtubules their particular metastable character. This work will lead to a rational understanding of the functional mechanisms of microtubule dynamics and may reveal the underlying mechanism of microtubule stabilization, eventually allowing development of new, more effective drugs targeted to tubulin.