Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

Gong, R.; Jiang, F.; Moreland, Z. G.; Reynolds, M. J.; Espinosa de los Reyes, S.; Gurel, P. S.; Shams, A.; Bowl, M. R.; Bird, J. E.; Alushin, G. M.

doi:10.1101/2021.07.09.451843

bioRxiv · 10.1101/2021.07.09.451843

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

Gong, R.·Jiang, F.·Moreland, Z. G.·Reynolds, M. J.·Espinosa de los Reyes, S.·Gurel, P. S.·Shams, A.·Bowl, M. R.·Bird, J. E.·Alushin, G. M.

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Abstract

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 actins 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 actins 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, R., Jiang, F., Moreland, Z. G., Reynolds, M. J., Espinosa de los Reyes, S., Gurel, P. S., Shams, A., Bowl, M. R., Bird, J. E., Alushin, G. M.. 2021-07-10. Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia. https://doi.org/10.1101/2021.07.09.451843

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