A conformational transition in the myosin VI converter contributes to the variable step size

V. Ovchinnikov, M. Cecchini, E. Vanden-Eijnden, M. Karplus

Research output: Contribution to journalArticle

Abstract

Myosin VI (MVI) is a dimeric molecular motor that translocates backwards on actin filaments with a surprisingly large and variable step size, given its short lever arm. A recent x-ray structure of MVI indicates that the large step size can be explained in part by a novel conformation of the converter subdomain in the prepowerstroke state, in which a 53-residue insert, unique to MVI, reorients the lever arm nearly parallel to the actin filament. To determine whether the existence of the novel converter conformation could contribute to the step-size variability, we used a path-based free-energy simulation tool, the string method, to show that there is a small free-energy difference between the novel converter conformation and the conventional conformation found in other myosins. This result suggests that MVI can bind to actin with the converter in either conformation. Models of MVI/MV chimeric dimers show that the variability in the tilting angle of the lever arm that results from the two converter conformations can lead to step-size variations of ∼12 nm. These variations, in combination with other proposed mechanisms, could explain the experimentally determined step-size variability of ∼25 nm for wild-type MVI. Mutations to test the findings by experiment are suggested.

Original languageEnglish (US)
Pages (from-to)2436-2444
Number of pages9
JournalBiophysical journal
Volume101
Issue number10
DOIs
StatePublished - Nov 16 2011

ASJC Scopus subject areas

  • Biophysics

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