Kinesins are eukaryotic cytoskeletal proteins best known for their motile activity, but they are also important regulators of microtubule (MT) dynamics, the ability of the MT polymer to grow or shrink. This project seeks to establish the molecular mechanism of microtubule (MT) dynamics regulation by members of the kinesin superfamily. Regulation of MT 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 MTs are not fully clear. We will test the general hypothesis that all these kinesin affect MT-dynamics by modifying the structure of tubulin to favor or disfavor the formation of the inter-tubulin contacts that hold the MT polymer together. To address this hypothesis we will use electron microscopy and other approaches to determine the structure of tubulin complexes of three model kinesins. The proposal has two general aims. The fist aim is to establish the mechanism of MT depolymerization by the kinesins KLP10A and Kar3.
The second aim addresses the mechanism of MT stabilization by the kinesin KIF14.

Public Health Relevance

The proposed work will investigate the molecular structure and mechanism of action of a group of kinesin proteins that modulate the ability of the microtubular cytoskeleton to elongate and shrink. Due to the role that these kinesins have in cell division and tumor growth they are also attractive targets for the development of anti-cancer drugs. Thus, the proposed studies may help the rational design of a new generation of drugs to treat cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM113164-04
Application #
9230400
Study Section
Special Emphasis Panel (ZRG1-BCMB-W (02)M)
Program Officer
Flicker, Paula F
Project Start
2015-03-01
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
4
Fiscal Year
2017
Total Cost
$363,726
Indirect Cost
$145,926
Name
Albert Einstein College of Medicine, Inc
Department
Type
Domestic Higher Education
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Chatterjee, Chandrima; Benoit, Matthieu P M H; DePaoli, Vania et al. (2016) Distinct Interaction Modes of the Kinesin-13 Motor Domain with the Microtubule. Biophys J 110:1593-604