文章基本信息

标题：Myosin VI deafness mutation prevents the initiation of processive runs on actin
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作者：Olena Pylypenko ; Lin Song ; Ai Shima 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：E1201-E1209
DOI：10.1073/pnas.1420989112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceA number of molecular motors transport cargoes long distances on their cellular tracks as single, dimeric (two-headed) molecules. This processive movement requires specialized kinetic properties (high duty ratio) to ensure that each head of the dimeric motor spends most of its time tightly bound to its track. Additionally, processive motors exhibit intramolecular communication between the heads, called gating, whose importance is less clear. By examining a mutation in the reverse-direction myosin motor, myosin VI, that causes deafness, we provide evidence that the mutation destroys the initiation of processive runs under physiological ATP concentration. We further demonstrate that this defect may be amendable to correction by small-molecule therapeutics. 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.
关键词：unconventional myosin ; deafness ; motility ; processive movement ; omecamtiv