Key result
Cryo-EM structures reveal that wild-type myosin-15 enhances actin polymerization by modulating actin's structural plasticity in a nucleotide-dependent manner, a process disrupted by the jordan deafness mutation.
Why the study?
To provide a structural framework for interpreting myosin-15 deafness mutations and their impacts on myosin-stimulated actin assembly in mechanosensory stereocilia.
Cryo-EM structures reveal that myosin-15 regulates actin polymerization by modulating actin's structural plasticity, providing a structural basis for how deafness mutations like jordan disrupt stereocilia elongation.
Structural insights into myosin-15 do not alter deafness management; leaves open targeted therapies pending cellular and in vivo validation.
Summary The motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and myosin-15 mutations cause profound deafness. In a companion study, we report that myosin-15 nucleates actin filament (“F-actin”) assembly and identify a progressive hearing loss mutation (p.D1647G, “ jordan ”) which disrupts stereocilia elongation by inhibiting actin polymerization. Here, we present cryo-EM structures of myosin-15 bound to F-actin, providing a framework for interpreting deafness mutations and their impacts on myosin-stimulated actin assembly. Rigor myosin-15 evokes conformational changes in F-actin yet maintains flexibility in actin’s D-loop, which mediates inter-subunit contacts, while the jordan mutant locks the D-loop in a single conformation. ADP-bound myosin-15 also locks the D-loop, which correspondingly blunts actin-polymerization stimulation. We propose myosin-15 enhances polymerization by bridging actin protomers, regulating nucleation efficiency by modulating actin’s structural plasticity in a myosin nucleotide-state dependent manner. This tunable regulation of actin polymerization could be harnessed to precisely control stereocilium height.
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Gong et al. (2021) studied Deafness (DFNB3). Myosin-15 (wild-type and jordan mutant) vs. Actin alone was evaluated on Cryo-EM structure resolution and actin polymerization dynamics. Cryo-EM structures reveal that wild-type myosin-15 enhances actin polymerization by modulating actin's structural plasticity in a nucleotide-dependent manner, a process disrupted by the jordan deafness mutation.
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