An atomic-level mechanism for activation of the kinesin molecular motors
Charles V. Sindelar1,2 and Kenneth H. Downing
-Author Affiliations
Life Sciences Division, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA 94720
↵2Present address: MS 029, Rosenstiel Center Department of Biochemistry MS 029, Rosenstiel Center, Brandeis University, 415 South Street, Waltham MA 02454-9110
Edited by Ronald D Vale, University of California-San Francisco, San Francisco, CA, and approved December 30, 2009 (received for review September 29, 2009)
Abstract
Kinesin cytoskeletal motors convert the energy of ATP hydrolysis into stepping movement along microtubules. A partial model of this process has been derived from crystal structures, which show that movement of the motor domain relative to its major microtubule binding element, the switch II helix, is coupled to docking of kinesin’s neck linker element along the motor domain. This docking would displace the cargo in the direction of travel and so contribute to a step. However, the crystal structures do not reveal how ATP binding and hydrolysis govern this series of events.
A molecular motor gives up its secrets. Electron microscope images of kinesin, one of life's smallest molecular motors, have been used to derive new, highly detailed 3-D maps (transparent surface) of the motor frozen in action. By fitting atomic models (colored ribbons) into the 3-D maps, a detailed mechanism has been derived for how a single molecule of biological fuel, called ATP, initiates motor movement. (Credit: Image by Charles Sindelar, Brandeis University) Source: Science Daily
We used cryoelectron microscopy to derive 8–9 Å-resolution maps of four nucleotide states encompassing the microtubule-attached kinetic cycle of a kinesin motor. The exceptionally high quality of these maps allowed us to build in crystallographically determined conformations of kinesin’s key subcomponents, yielding novel arrangements of kinesin’s switch II helix and nucleotide-sensing switch loops. The resulting atomic models reveal a seesaw mechanism in which the switch loops, triggered by ATP binding, propel their side of the motor domain down and thereby elicit docking of the neck linker on the opposite side of the seesaw. Microtubules engage the seesaw mechanism by stabilizing the formation of extra turns at the N terminus of the switch II helix, which then serve as an anchor for the switch loops as they modulate the seesaw angle. These observations explain how microtubules activate kinesin’s ATP-sensing machinery to promote cargo displacement and inform the mechanism of kinesin’s ancestral relative, myosin.
ATPase cryoelectron microscopy motility myosin structure
Footnotes
1To whom correspondence should be addressed. E-mail:sindelar@brandeis.edu.
Author contributions: C.V.S. and K.H.D. designed research; C.V.S. performed research; C.V.S. contributed new reagents/analytic tools; C.V.S. analyzed data; C.V.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: Density maps have been deposited in EMDB, http://emsearch.rutgers.edu (accession nos. 5164–5167).
This article contains supporting information online at www.pnas.org/cgi/content/full/0911208107/DCSupplemental.
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