Kinesins move along microtubules or depolymerize them from the ends. Over the last 12 years, we have used cryo-electron microscopy and image analysis to investigate these motility and depolymerization activities. Based on our findings, as well as work from many other laboratories, we have outlined design principles that unify our thinking about kinesins and myosins and provide a general framework for a mechanistic understanding of these two superfamilies of molecular motors. We now have a good general understanding of the nucleotide-mediated conformational changes underlying processive, plus-end-directed motion by conventional kinesin, non-processive, minus-end-directed motion by kinesin 14s, and many aspects of kinesin 13-mediated depolymerization. Additional work on microtubule associated proteins has provided insights into the mechanisms of selective microtubule stabilization by these proteins. Our past results set the stage for the current proposal. The experiments described here fall into two broad subject areas. First, we describe experiments that will answer what we see as some of the remaining outstanding general questions about kinesin-mediated motility and depolymerization. Second, we build upon our investigations on MAPs, expanding this aspect of our research program and incorporating studies on microtubule plus-end-tracking proteins and kinetochore complexes to investigate the structural basis for modulation of microtubule dynamics and chromosome-microtubule attachments. In all our work, we seek to answer fundamental biological questions and our findings have relevance for both the healthy and diseased states.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Cell Structure and Function (CSF)
Program Officer
Deatherage, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Kern, David M; Monda, Julie K; Su, Kuan-Chung et al. (2017) Astrin-SKAP complex reconstitution reveals its kinetochore interaction with microtubule-bound Ndc80. Elife 6:
Monda, Julie K; Whitney, Ian P; Tarasovetc, Ekaterina V et al. (2017) Microtubule Tip Tracking by the Spindle and Kinetochore Protein Ska1 Requires Diverse Tubulin-Interacting Surfaces. Curr Biol 27:3666-3675.e6
Wilson-Kubalek, Elizabeth M; Cheeseman, Iain M; Milligan, Ronald A (2016) Structural comparison of the Caenorhabditis elegans and human Ndc80 complexes bound to microtubules reveals distinct binding behavior. Mol Biol Cell 27:1197-203
Garnham, Christopher P; Vemu, Annapurna; Wilson-Kubalek, Elizabeth M et al. (2015) Multivalent Microtubule Recognition by Tubulin Tyrosine Ligase-like Family Glutamylases. Cell 161:1112-1123
Hsia, Kuo-Chiang; Wilson-Kubalek, Elizabeth M; Dottore, Alejandro et al. (2014) Reconstitution of the augmin complex provides insights into its architecture and function. Nat Cell Biol 16:852-63
Schmidt, Jens C; Arthanari, Haribabu; Boeszoermenyi, Andras et al. (2012) The kinetochore-bound Ska1 complex tracks depolymerizing microtubules and binds to curved protofilaments. Dev Cell 23:968-80
Vadia, Stephen; Arnett, Eusondia; Haghighat, Anne-C├ęcile et al. (2011) The pore-forming toxin listeriolysin O mediates a novel entry pathway of L. monocytogenes into human hepatocytes. PLoS Pathog 7:e1002356
Chappie, Joshua S; Mears, Jason A; Fang, Shunming et al. (2011) A pseudoatomic model of the dynamin polymer identifies a hydrolysis-dependent powerstroke. Cell 147:209-22
Fisher, Lauren S; Ward, Andrew; Milligan, Ronald A et al. (2011) A helical processing pipeline for EM structure determination of membrane proteins. Methods 55:350-62
Mulder, Anke M; Yoshioka, Craig; Beck, Andrea H et al. (2010) Visualizing ribosome biogenesis: parallel assembly pathways for the 30S subunit. Science 330:673-7

Showing the most recent 10 out of 39 publications