Reports

Closing of the Nucleotide Pocket of Kinesin-Family Motors upon Binding to Microtubules

Nariman Naber,^1* Todd J. Minehardt,⁵ Sarah Rice,² Xiaoru Chen,⁶ Jean Grammer,⁶ Marija Matuska,¹ Ronald D. Vale,² Peter A. Kollman,³ Roberto Car,⁵ Ralph G. Yount,^6,7 Roger Cooke,^1,4 Edward Pate⁸

We have used adenosine diphosphate analogs containing electron paramagnetic resonance (EPR) spin moieties and EPR spectroscopy to show that the nucleotide-binding site of kinesin-family motors closes when the motor·diphosphate complex binds to microtubules. Structural analyses demonstrate that a domain movement in the switch 1 region at the nucleotide site, homologous to domain movements in the switch 1 region in the G proteins [heterotrimeric guanine nucleotide–binding proteins], explains the EPR data. The switch movement primes the motor both for the free energy–yielding nucleotide hydrolysis reaction and for subsequent conformational changes that are crucial for the generation of force and directed motion along the microtubule.

¹ Department of Biochemistry, University of California, San Francisco, CA 94143, USA.
² Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
³ Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA.
⁴ Cardiovascular Research Institute, University of California, San Francisco, CA 94143, USA.
⁵ Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
⁶ School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
⁷ Department of Chemistry, Washington State University, Pullman, WA 99164, USA.
⁸ Department of Mathematics, Washington State University, Pullman, WA 99164, USA.

Present address: Department of Chemistry, University of Colorado, Denver, CO 80217, USA.

Deceased.

^* To whom correspondence should be addressed. E-mail: naber{at}itsa.ucsf.edu

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A kinesin-13 mutant catalytically depolymerizes microtubules in ADP.

M. Wagenbach, S. Domnitz, L. Wordeman, and J. Cooper (2008)
J. Cell Biol. 183, 617-623
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Backsteps induced by nucleotide analogs suggest the front head of kinesin is gated by strain.

N. R. Guydosh and S. M. Block (2006)
PNAS 103, 8054-8059
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The Sliding Filament Model: 1972-2004.

R. Cooke (2004)
J. Gen. Physiol. 123, 643-656
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Crystal Structure of Kinesin Regulated by Ca2+-Calmodulin.

M. V. Vinogradova, V. S. Reddy, A. S. N. Reddy, E. P. Sablin, and R. J. Fletterick (2004)
J. Biol. Chem. 279, 23504-23509
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Kinesin's second step.

L. M. Klumpp, A. Hoenger, and S. P. Gilbert (2004)
PNAS 101, 3444-3449
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A comparative study of motor-protein motions by using a simple elastic-network model.

W. Zheng and S. Doniach (2003)
PNAS 100, 13253-13258
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