期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 24, 页码 6213-6218出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1711512115
关键词
molecular motors; chemomechanical transduction; myosin; recovery stroke; molecular dynamics simulations
资金
- National Institutes of Health [DC009100]
- Fondation pour la Recherche Medicale [DBI20141231319]
- Agence Nationale de la Recherche (ANR) through the LabEx Chemistry of Complex Systems [CSC-MCE-13]
- International Center for Frontier Research in Chemistry
- Association Francaise Contre les Myopathies [17235]
- Initiative d'Excellence Paris Sciences et Lettres [ANR-10-IDEX-0001-02 PSL]
- French Ministry of Higher Education and Research
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 A 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 compared with the prerecovery state. These results support the conclusion that closing of switch II does not initiate the recovery stroke transition in myosin VI. Rather, they suggest a mechanism in which lever arm repriming would be mostly driven by thermal fluctuations and eventually stabilized by the switch II interaction with the nucleotide in a ratchet-like fashion.
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