期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 11, 页码 E1201-E1209出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420989112
关键词
unconventional myosin; deafness; motility; processive movement; omecamtiv
资金
- Association de la Recherche contre le Cancer (ARC) postdoctoral fellowship
- NIH [DC009100]
- CNRS
- ARC subvention fixe [(ARC 1067) 1067XA0830F]
- Fondation pour la Recherche Medicale Equipe grant
- Agence Nationale de la Recherche Blanche BLAN
Mutations in the reverse-direction myosin, myosin VI, are associated with deafness in humans and mice. A myosin VI deafness mutation, D179Y, which is in the transducer of the motor, uncoupled the release of the ATP hydrolysis product, inorganic phosphate (Pi), from dependency on actin binding and destroyed the ability of single dimeric molecules to move processively on actin filaments. We observed that processive movement is rescued if ATP is added to the mutant dimer following binding of both heads to actin in the absence of ATP, demonstrating that the mutation selectively destroys the initiation of processive runs at physiological ATP levels. A drug (omecamtiv) that accelerates the actin-activated activity of cardiac myosin was able to rescue processivity of the D179Y mutant dimers at physiological ATP concentrations by slowing the actin-independent release of Pi. Thus, it may be possible to create myosin VI-specific drugs that rescue the function of deafness-causing mutations.
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