The protein tubulin plays a vital role in the life of all eukaryotic cells. Microtubules, made mostly of tubulin, are involved, for example, in organelle movement, separation of chromosomes during cell division, and maintenance of cell shape. 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 a 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. Through studies of tubulin in complexes with ligands such as aluminum fluoride and pentalysine, and using genetic manipulation, we will investigate factors that give microtubules their particular metastable character. We will study the interaction of tubulin with drugs that stabilize microtubules and the interactions with some of the proteins that regulate the microtubule cytoskeleton. 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.
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