DESCRIPTION (provided by applicant): Kinesins comprise a diverse superfamily of over one hundred different proteins, all containing a highly conserved globular catalytic domain with ATPase and microtubule binding activities. Despite the high degree of homology and similar three-dimensional structure of their motor domains, there is considerable functional variability among different kinesins. Most kinesins, such as kinesin1s and kinesin5s, move and generate force along microtubules (walkers), but some, such as kinesin13s, actively depolymerize microtubules (depolymerases). It is not clear how very similar catalytic domains (sequence and 3D structure) present throughout the kinesin superfamily can perform these two very different functions. To address this issue in this project we will apply several biophysical and cell biology techniques to investigate structural and functional characteristic of kinesin13s and kinesin5s. We will address the following questions: 1) What is the structural basis of the stabilization of tubulin curvature by the kinesin13 motor domain? 2) What is the physiological role of the recently described microtubule-ring complexes, unique to the kinesin13 family? 3) What is the mechanism of kinesin13 one-dimensional diffusion (ODD) on the microtubule lattice? 4) Is the translocation mechanism of kinesin5 different from other kinesin walkers, such as kinesin1? The proposed studies will reveal how different protein domains and secondary structure elements in the two kinesin types lead to their different functionality. Both kinesin5 and kinesin13 are potential targets for anti-tumor chemotherapy. Thus, the proposed studies may provide new insights to develop more effective therapies against cancer. PUBLIC HEALTH RELEVANCE: This project seeks to elucidate the mechanism of action of two different motor proteins, the kinesin5s and the kinesin13s. These kinesins are important during cell division and are potential targets for anti-cancer drugs. Understanding how these proteins work may help finding better treatments for cancer.
|Effective start/end date||9/1/09 → 6/30/10|
- National Institute of General Medical Sciences: $399,721.00
- Drug Discovery
- Structural Biology
- Cell Biology