Other Perelman School of Medicine Affiliations
Biochemistry and Molecular Biophysics Graduate Program
Cell and Molecular Biology Graduate Group
Pennsylvania Muscle Institute
M.S., Moscow State University, 1990
Ph.D., University of Colorado at Boulder, 1997
Honors and Awards
Kimmel Scholar Award, 2011-Present
McCabe Pilot Award, 2010
17th Annual MBC Paper of the Year Award, 2008
ASCB Celldance, 2nd place Video, 2008
Dean's Small Grant Award, Univ. of Colorado at Boulder, 1992, 1993
American Society for Cell Biology (ASCB)
During cell division the chromosomes must segregate equally to ensure health and viability of two daughter cells. This vital goal is achieved by elaborate cytoskeletal machine, the mitotic spindle. First, spindle microtubules attach to kinetochores on duplicated sister chromosomes. Then microtubules shorten and two identical sets of now separated sister chromosomes become transported to the opposite poles of a dividing cell, producing two genetically identical daughters. The main goal of the research in our lab is to understand the molecular mechanisms that produce force and accuracy for mitotic chromosome motions. This research is fundamentally important not only because cell division is a key process of cellular and developmental biology, but also because controlling the factors that ensure equal chromosome segregation is of great medical significance. Indeed, the mitotic spindle constitutes one of the major chemotherapeutic targets, so a rigorous understanding of the kinetochore-microtubule attachments should ultimately assist developing novel and more specific anticancer drugs.
Our work toward this goal relies on a combination of biophysical, cell biological and computational approaches. We have previously used laser trap and microtubule polymers in vitro to show that disassembling microtubules can exert enough force to explain chromosome motions in cells. However, the shortening microtubule ends must be harnessed appropriately to the kinetochore. Our working hypothesis is that molecular and biomechanical properties of kinetochore proteins are optimized to enable them to function as efficient nanomachines, which capture the energy from microtubule disassembly and provide lasting attachments to the shortening microtubule ends. There are no man-made or natural macro-devices that function analogously to these couplers, so understanding their principle mechanisms presents a significant conceptual challenge and requires multidisciplinary and multi-faceted approaches.
With versatile laser trapping and single molecule techniques, we study interactions between dynamic microtubules and purified kinetochore proteins in vitro under conditions that mimic kinetochore-microtubule interactions in live cells. Current research is focused on the kinetochore-localized kinesin motor CENP-E and microtubule-binding proteins Ndc80 and Ska1. With Total Internal Reflection Fluorescent microscopy we examine ability of these proteins to stay attached to dynamic ends of microtubule polymers. These proteins are also conjugated to microbeads, representing greatly simplified kinetochores, and these beads are manipulated with laser tweezers to measure and exert controllable forces. We hope that our studies will provide a conceptual framework for understanding in general how the mitotic chromosomes maintain reliable links with dynamic microtubule ends and how much of this behavior can be attributed to specific kinetochore components.
Gudimchuk, N., Vitre, N., Kim, Y., Kiyatkin, A., Cleveland, D.W., Ataullakhanov, F.I. and E. L. Grishchuk: Kinetochore kinesin CENP-E is a processive bi-directional tracker of dynamic microtubule tips. Nature Cell Biology 15(9):1030-2, Sep 2013.
Volkov, V.A., Zaytsev, A.V., Gudimchuk, N., Grissom, P.M., Gintsburg, A.L., Ataullakhanov, F.I., McIntosh, J.R. and E.L. Grishchuk: Long tethers provide high-force coupling of the Dam1 ring to shortening microtubules. PNAS 110(19): 7708-13, May 2013.
Schmidt, J.C., Arthanari, H., Boeszoermenyi, A., Dashkevich, N.M., Wilson-Kubalek, E.M., Monnier, N., Markus, M., Oberer, M., Milligan, R.A., Bathe, M., Wagner, G., Grishchuk, E.L. and I.M. Cheeseman: The kinetochore-bound Ska1 complex tracks depolymerizing microtubules and binds to curved protofilaments. Developmental Cell 23(5): 968-80, Nov 2012.
Grishchuk, E.L., McIntosh, J.R., Molodtsov, M.I. and F.I. Ataullakhanov: Force generation by dynamic microtubule polymers. In Comprehensive Biophysics vol. 4: 93-117. Eds. E.M. Ostap and Y.E. Goldman. Elsevier, May 2012. (ISBN: 978-0-08-095718-0)
McIntosh, J.R., Volkov, V., Ataullakhanov, F.I., and E.L. Grishchuk, E.L: Tubulin depolymerization may be an ancient biological motor. Journal of Cell Science 123(Pt20): 3425-34. Oct 2010.
Grishchuk, E.L., Efremov, A.K., Volkov, V.A., Spiridonov, I.S., Gudimchuk, N., Westermann, S., Drubin, D., Barnes, G., McIntosh, J.R. and F.I. Ataullakhanov: The Dam1 ring binds microtubules strongly enough to be a processive as well as energy-efficient coupler for chromosome motion. PNAS 105(40): 15423-8, Oct 2008.
McIntosh, J.R., Grishchuk, E.L., Morphew, M., Efremov, A., Zhudenkov, K., Volkov, V.A., Cheeseman, I.M., Desai, A., Mastronarde, D. and F.I. Ataullakhanov: Fibrils connect microtubule tips with kinetochores: a mechanism to couple tubulin dynamics to chromosome motion. Cell 135(2): 322-33, Oct 2008.
Efremov, A., Grishchuk, E.L., McIntosh, J. R. and F. I. Ataullakhanov: In search of an optimal ring to couple microtubule depolymerization to processive chromosome motions. PNAS 104(48): 19017-22, Nov 2007.
Grishchuk, E.L. and J.R. McIntosh: Microtubule depolymerization can drive poleward chromosome motion in fission yeast. The EMBO journal 25(20): 4888-96, Oct 2006.
Grishchuk, E.L., Molodtsov, M.I., Ataullakhanov, F.I., and J.R. McIntosh: Force production by disassembling microtubules. Nature 438(7066): 384-8, Nov 2005.
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