Mechanism of Microtubule Dynamics Regulation by Kinesins

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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 mechanism of microtubule dynamics regulation by members of the kinesin superfamily. Regulation of microtubule dynamics by these kinesins play important roles in a variety of cell processes such as mitosis, cytokinesis, neural development and control of cilia and centriole length, but the mechanisms by which these kinesins stabilize or destabilize microtubules is still not clear. It is not known how different kinesin may be adapted for seemingly different functionalities or whether they share common mechanisms. To address this issue we propose to conduct comparative structural and functional analysis of several kinesins with distinct functionalities: the microtubule depolymerase KLP10A (kinesin-13), the motile and microtubule stabilizers KIF14 (kinesin-3) and EG5 (kinesin- 5) and the archetypical motile kinesin KIF5B (kinesin-1). The proposal is divided in four aims. The first two aims test the hypothesis based on our recent work that the same ATPase related confomational changes occurring in the motor domain of kinesin-1s are adapted in kinesin-13s to depolymerize microtubules. The second aim investigates the mechanism by which EG5 promotes microtubule polymerization and inhibits depolymerization. The fourth aim uses cryo- em structural analysis to guide the development and optimization of KIF14 specific drugs for research and potentially clinical use.