Mechanism of Microtubule Dynamics Regulation by Kinesins

Kinesins are eukaryotic cytoskeletal proteins best known for their motile activity, but they are also important regulators of microtubule dynamics, the ability of the microtubule polymer to grow or shrink. This project seeks to establish the molecular mechanisms and adaptations that allows different members of the kinesin superfamily to move along microtubules or to modulate microtubule dynamics. Regulation of microtubule dynamics by kinesins play important roles in a variety of cell processes such as mitosis, cytokinesis, neural development and the control of cilia and centriole length, but the mechanisms by which these kinesins stabilize or destabilize microtubules is still not fully clear. It is also not clear what conformational changes kinesins induce on the microtubule and whether these conformational changes are transmitted through the microtubule to allosterically modulate the binding of kinesin and other proteins along microtubules. To address these questions, we will perform cryo-electron microscopy structural and functional studies of motile and microtubule depolymerase kinesins, and their effect on microtubule structure. The proposal is divided into three aims: 1) Determine the allosteric effects of kinesin binding on microtubule structure and function. 2) Determine the mechanism of combined motile and microtubule depolymerization activities of Kinesin-8s. 3) Determine the origin of different functionalities among microtubule depolymerase kinesins.