An intermediate along the recovery stroke of myosin VI revealed by X-ray crystallography and molecular dynamics

Proceedings of the National Academy of Sciences of the United States of America
Florian BlancAnne Houdusse

Abstract

Myosins form a class of actin-based, ATPase motor proteins that mediate important cellular functions such as cargo transport and cell motility. Their functional cycle involves two large-scale swings of the lever arm: the force-generating powerstroke, which takes place on actin, and the recovery stroke during which the lever arm is reprimed into an armed configuration. Previous analyses of the prerecovery (postrigor) and postrecovery (prepowerstroke) states predicted that closure of switch II in the ATP binding site precedes the movement of the converter and the lever arm. Here, we report on a crystal structure of myosin VI, called pretransition state (PTS), which was solved at 2.2 Å resolution. Structural analysis and all-atom molecular dynamics simulations are consistent with PTS being an intermediate along the recovery stroke, where the Relay/SH1 elements adopt a postrecovery conformation, and switch II remains open. In this state, the converter appears to be largely uncoupled from the motor domain and explores an ensemble of partially reprimed configurations through extensive, reversible fluctuations. Moreover, we found that the free energy cost of hydrogen-bonding switch II to ATP is lowered by more than 10 kcal/mol compare...Continue Reading

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Citations

Sep 12, 2019·Proceedings of the National Academy of Sciences of the United States of America·Wonmuk Hwang, Martin Karplus
Sep 5, 2020·International Journal of Molecular Sciences·Raudah LazimSun Choi
Jan 23, 2021·The Journal of Physical Chemistry. B·Mauro Lorenzo Mugnai, D Thirumalai
Dec 31, 2020·International Journal of Molecular Sciences·Peter FranzGeorgios Tsiavaliaris
Mar 26, 2021·The Journal of Physical Chemistry Letters·Florian E Blanc, Marco Cecchini
Nov 7, 2019·Chemical Reviews·Julien Robert-PaganinAnne Houdusse

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