Key result
Mutation of leucine 310 to glycine in Myosin VI removes the influence of insert-1 on ATP binding, suggesting nucleotides initially bind via purine rings before docking phosphate moieties.
This study elucidates the molecular mechanism by which insert-1 and leucine 310 in Myosin VI selectively hinder ATP versus ADP binding.
No direct clinical application yet; leaves open generalization to cardiac myosins or therapies.
Myosin VI is unique in its directionality among myosin superfamily members and also displays a slow and strain-dependent rate of ATP binding that allows for gating between its heads. In this study we demonstrate that leucine 310 is positioned by a class VI-specific insert, insert-1, so as to account for the selective hindrance of ATP versus ADP binding. Mutation of leucine 310 to glycine removes all influence of insert-1 on ATP binding. Furthermore, by analyzing myosin VI structures with either leucine 310 substituted to a glycine or complete removal of insert-1, we conclude that nucleotides may initially bind to myosin by their purine rings before docking their phosphate moieties. Otherwise, insert-1 could not exert a differential influence on ATP versus ADP binding.
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Pylypenko et al. (2011) studied Myosin VI nucleotide affinity. Mutation of leucine 310 to glycine or removal of insert-1 vs. Wild-type Myosin VI was evaluated on ATP versus ADP binding affinity. Mutation of leucine 310 to glycine in Myosin VI removes the influence of insert-1 on ATP binding, suggesting nucleotides initially bind via purine rings before docking phosphate moieties.
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