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 and microtubules by electron crystallography and cryo-EM. 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 bind to microtubules and that utilize and regulate the microtubule cytoskeleton. This work will lead to a rational understanding of the functional mechanisms of microtubule dynamics and may reveal several distinct underlying mechanism of microtubule stabilization, eventually allowing development of new, more effective drugs targeted to tubulin.
Our structural studies of tubulin and the microtubules it forms are aimed at understanding how proteins and small ligands interact in regulating processes within cells. This information will expand our knowledge of basic cell biology and enhance opportunities to address diseases including cancer and Parkinson's Disease..
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