Clues to molecular motor movement

The movement of molecular motors that carry a cell's cargo may be controlled in a different manner than previously suspected, according to a paper in this week's Science. The molecular motor kinesin, which carries vesicles, organelles, and other loads along cellular microtubule networks, may not need the networks themselves to move -- a finding that "throws a surprising wrench into existing models of kinesin movement," according to an accompanying commentary by David Hackney of Carnegie Mellon University in Pittsburgh.Kinesin consists of two components, called "heads," that walk in a hand-over-hand fashion along microtubules. Kinesin powers this movement by hydrolyzing adenosine triphosphate (ATP), consuming one molecule per step. Between steps, the motor pauses, and is stalled until ATP binds to a kinesin head. But the exact mechanism for how this ATP "gating" occurs has been controversial. Researchers have proposed two general mechanisms for the ATP gate. In the first, kinesin stops between steps with only one head attached to the microtubule. The other head is loosely tethered and cannot reach its next binding site until ATP induces a conformational change in kinesin that shifts it along the microtubule. In the second mechanism, kinesin stops between steps with both heads attached to the microtubule, and the resulting strain between the two attached heads prevents the motor from moving forward until ATP binds to one of the heads. In both models, ATP binding is thought to trigger kinesin's next step "by a mechanism that requires the microtubule lattice," senior author Robert Cross of the Marie Curie Research Institute in Cambridge, UK, told The Scientist in an Email.Led by Maria Alonso, also of the Marie Curie Research Institute, the researchers found that this microtubule lattice does not appear to be necessary for ATP control of kinesin movement. The researchers instead found that tubulin subunits -- the components of microtubules -- can induce the ATP cycle on their own, without being assembled into microtubules.Gel filtration experiments showed that unpolymerized tubulin binds to kinesin in solution. When the researchers measured ATPase activity in the solution, they found that free tubulin drives hydrolyzation of ATP at the kinesin head, just as what happens when kinesin is bound to microtubules. Because free tubulin can activate the kinesin ATP cycle, the authors say that neither previous theory of kinesin movement is correct, because both require that the kinesin heads interact with assembled microtubules."Our findings show that microtubule geometry is completely irrelevant to the gating mechanism," Cross said. Instead of ATP releasing strain between the kinesin heads, the researchers suspect that the microtubule binding site on one kinesin head is masked until ATP binding to the other head unblocks the masked site. "In the pauses between steps, only one head of each kinesin molecule can bind to microtubules," Cross explained. "We think the other head may park against its partner. ATP binding unblocks the microtubule binding site on the second head... allowing it to bind to the next available binding site along the microtubule."According to Steven Block of Stanford University in California, who was not involved in the work, the study's results do not rule out the involvement of strain in the motor's movements. Even though the experiments used free tubulin instead of microtubules, it's possible that simply being attached to tubulin subunits causes some sort of strain between the kinesin heads, Block, who has published research discussing the effect of strain on kinesin movement, told The Scientist. "The analogy is like asking somebody to walk with really big snowshoes on each of their feet," Block said. "They may be free to move about, but the heads are not free to move in the way that they normally move." It's also possible that the tubulin subunits briefly polymerize into tiny microtubules, Block said. The authors didn't see any polymerization, but microtubules could form very briefly or in such short stretches that they couldn't be seen by microscopy, Block said.The researchers' results do suggest that kinesin's movement can be controlled without strain between the two heads, said Steven Rosenfeld of Columbia University in New York, who wasn't involved in the work, but that doesn't mean it's the only way that movement is regulated in vivo. "There may be multiple steps in the ATP cycle where the motor is gated," some involving strain and some not, Rosenfeld said. "The bigger question is where this piece of information fits in the overall scheme of how kinesin works."Melissa Lee Phillips mail@the-scientist.comLinks within this article:J.M. Perkel, "Investigating molecular motors step by step," The Scientist, March 15, 2004. http://www.the-scientist.com/2004/3/15/19/1/M.C. Alonso et al., "An ATP gate controls tubulin binding by the tethered head of kinesin-1," Science, April 6, 2007. http://www.sciencemag.orgJ. Yajnik, "Walking revolution," The Scientist, October 1, 2006. http://www.the-scientist.com/2006/10/1/70/1/D.D. Hackney, "Processive motor movement," Science, April 6, 2007. http://www.sciencemag.orgDavid Hackney http://www.cmu.edu/bio/contacts/faculty/hackney.shtmlP.R. Selvin, "Walk like a molecular motor," The Scientist, June 20, 2005. http://www.the-scientist.com/article/display/15546/N.J. Carter, R.A. Cross, "Kinesin's moonwalk," Current Opinion in Cell Biology, February 2006. http://www.the-scientist.com/pubmed/16361092S. Rice et al., "A structural change in the kinesin motor protein that drives motility," Nature, December 16, 1999. http://www.the-scientist.com/pubmed/10617199S.S. Rosenfeld et al., "Stepping and stretching. How kinesin uses internal strain to walk processively," Journal of Biological Chemistry, May 16, 2003. http://www.the-scientist.com/pubmed/12626516Robert Cross http://mc11.mcri.ac.uk/motorhome.htmlSteven Block http://www.stanford.edu/group/blocklab/Steven Rosenfeld http://156.111.235.11/pharm/cumc/profile.php?id=259

Clues to molecular motor movement

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