Myosin VI deafness mutation prevents the initiation of processive runs on actin

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Pylypenko, Olena | Song, Lin | Shima, Ai | Yang, Zhaohui | Houdusse, Anne | Sweeney, H, Lee

Edité par CCSD ; National Academy of Sciences -

International audience. 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 (P i), 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 P i. Thus, it may be possible to create myosin VI-specific drugs that rescue the function of deafness-causing mutations. unconventional myosin | deafness | motility | processive movement | omecamtiv Data deposition: Crystallography, atomic coordinates, and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4DBP, 4DBQ, and 4DBR).

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