Myosin VI deafness mutation prevents the initiation of processive runs on actin.
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.
Structural Motility, Centre de Recherche, Institut Curie, Paris F-75248, France; CNRS, UMR 144, 75248 Paris Cedex 5, France; and.
Olena
O
Pylypenko
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Lin
L
Song
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Ai
A
Shima
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Zhaohui
Z
Yang
Structural Motility, Centre de Recherche, Institut Curie, Paris F-75248, France; CNRS, UMR 144, 75248 Paris Cedex 5, France; and anne.houdusse@curie.fr Lsweeney@mail.med.upenn.edu.
Anne M
AM
Houdusse
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 anne.houdusse@curie.fr Lsweeney@mail.med.upenn.edu.
H Lee
HL
Sweeney
D000199:Actins / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D003638:Deafness / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D017434:Protein Structure, Tertiary; D034421:Sus scrofa; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D000199:Actins; D050505:Mutant Proteins; C089785:myosin VI; C547293:omecamtiv mecarbil; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D014508:Urea; D000251:Adenosine Triphosphatases; D018995:Myosin Heavy Chains
deafness; motility; omecamtiv; processive movement; unconventional myosin