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

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.

• Authors: Olena Pylypenko, Lin Song, Ai Shima, Zhaohui Yang, Anne M Houdusse, H Lee Sweeney
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 11 Pg. E1201-9 (Mar 17 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25751888 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Mutant Proteins
• myosin VI
• omecamtiv mecarbil
• Adenosine Diphosphate
• Adenosine Triphosphate
• Urea
• Adenosine Triphosphatases
• Myosin Heavy Chains

Topics

• Actins (metabolism)
• Adenosine Diphosphate (metabolism)
• Adenosine Triphosphatases (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Biomechanical Phenomena (drug effects)
• Deafness (genetics)
• Humans
• Kinetics
• Mice
• Models, Biological
• Models, Molecular
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Myosin Heavy Chains (chemistry, genetics, metabolism)
• Protein Multimerization (drug effects)
• Protein Structure, Tertiary
• Sus scrofa
• Urea (analogs & derivatives, pharmacology)