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, E.
AU - Karplus, M.
N1 - Funding Information:
The work done at Harvard was supported in part by a grant from the National Institutes of Health. A grant from the Human Frontiers Science Program supported the work done in Strasbourg. V.O. received a National Research Service Award (1F32GM083422-01). M.C. was supported by the International Center for Frontier Research in Chemistry (Strasbourg). E.V.-E. was supported by grants from the National Science Foundation (DMS-0708140) and the Office of Naval Research (N00114-04-1-6046).
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.
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U2 - 10.1016/j.bpj.2011.09.044
DO - 10.1016/j.bpj.2011.09.044
M3 - Article
C2 - 22098742
AN - SCOPUS:81255164918
SN - 0006-3495
VL - 101
SP - 2436
EP - 2444
JO - Biophysical journal
JF - Biophysical journal
IS - 10
ER -