The globular tail domain puts on the brake to stop the ATPase cycle of myosin Va

doi:10.1073/pnas.0709741105

The globular tail domain puts on the brake to stop the ATPase cycle of myosin Va

*Departments of Physiology and
^‡Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655

Edited by James A. Spudich, Stanford University School of Medicine, Stanford, CA, and approved December 10, 2007 (received for review October 15, 2007)

Abstract

Myosin Va is a well known processive motor involved in transport of organelles. A tail-inhibition model is generally accepted for the regulation of myosin Va: inhibited myosin Va is in a folded conformation such that the tail domain interacts with and inhibits myosin Va motor activity. Recent studies indicate that it is the C-terminal globular tail domain (GTD) that directly inhibits the motor activity of myosin Va. In the present study, we identified a conserved acidic residue in the motor domain (Asp-136) and two conserved basic residues in the GTD (Lys-1706 and Lys-1779) as critical residues for this regulation. Alanine mutations of these conserved charged residues not only abolished the inhibition of motor activity by the GTD but also prevented myosin Va from forming a folded conformation. We propose that Asp-136 forms ionic interactions with Lys-1706 and Lys-1779. This assignment locates the GTD-binding site in a pocket of the motor domain, formed by the N-terminal domain, converter, and the calmodulin in the first IQ motif. We propose that binding of the GTD to the motor domain prevents the movement of the converter/lever arm during ATP hydrolysis cycle, thus inhibiting the chemical cycle of the motor domain.

Footnotes

^†To whom correspondence should be addressed. E-mail: xiangdong.li{at}umassmed.edu
Author contributions: X.-d.L. designed research; X.-d.L., H.S.J., Q.W., and R.I. performed research; X.-d.L. and M.I. analyzed data; and X.-d.L., R.C., and M.I. wrote the paper.
↵ ^§Present address: Division of Molecular Medicine, Department of Medicine, Columbia University Medical Center, New York, NY 10032.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0709741105/DC1.