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

Proceedings of the National Academy of Sciences of the United States of America
Olena PylypenkoH Lee Sweeney

Abstract

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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Citations

Jan 27, 2016·Proceedings of the National Academy of Sciences of the United States of America·Christopher BattersClaudia Veigel
Mar 16, 2016·Proceedings of the National Academy of Sciences of the United States of America·Sarah F WulfRasmus R Schröder
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Feb 2, 2017·Proceedings of the National Academy of Sciences of the United States of America·Thomas A Masters, Folma Buss
Aug 5, 2017·Nature Communications·Vicente J Planelles-HerreroAnne Houdusse
May 31, 2018·Proceedings of the National Academy of Sciences of the United States of America·Florian BlancAnne Houdusse
May 18, 2017·Proceedings of the National Academy of Sciences of the United States of America·Mauro L Mugnai, D Thirumalai
Jan 23, 2021·The Journal of Physical Chemistry. B·Mauro Lorenzo Mugnai, D Thirumalai
Nov 7, 2019·Chemical Reviews·Julien Robert-PaganinAnne Houdusse

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