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

V. Ovchinnikov, M. Cecchini, Eric 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

Fingerprint

Actin Cytoskeleton
Myosins
myosin VI
Actins
X-Rays
Mutation

ASJC Scopus subject areas

  • Biophysics

Cite this

A conformational transition in the myosin VI converter contributes to the variable step size. / Ovchinnikov, V.; Cecchini, M.; Vanden Eijnden, Eric; Karplus, M.

In: Biophysical Journal, Vol. 101, No. 10, 16.11.2011, p. 2436-2444.

Research output: Contribution to journalArticle

Ovchinnikov, V. ; Cecchini, M. ; Vanden Eijnden, Eric ; Karplus, M. / A conformational transition in the myosin VI converter contributes to the variable step size. In: Biophysical Journal. 2011 ; Vol. 101, No. 10. pp. 2436-2444.
@article{7a113add1a844937bb91bd2025b66ce8,
title = "A conformational transition in the myosin VI converter contributes to the variable step size",
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.",
author = "V. Ovchinnikov and M. Cecchini and {Vanden Eijnden}, Eric and M. Karplus",
year = "2011",
month = "11",
day = "16",
doi = "10.1016/j.bpj.2011.09.044",
language = "English (US)",
volume = "101",
pages = "2436--2444",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "10",

}

TY - JOUR

T1 - A conformational transition in the myosin VI converter contributes to the variable step size

AU - Ovchinnikov, V.

AU - Cecchini, M.

AU - Vanden Eijnden, Eric

AU - Karplus, M.

PY - 2011/11/16

Y1 - 2011/11/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=81255164918&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81255164918&partnerID=8YFLogxK

U2 - 10.1016/j.bpj.2011.09.044

DO - 10.1016/j.bpj.2011.09.044

M3 - Article

C2 - 22098742

AN - SCOPUS:81255164918

VL - 101

SP - 2436

EP - 2444

JO - Biophysical Journal

JF - Biophysical Journal

SN - 0006-3495

IS - 10

ER -