TY - JOUR T1 - Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia JF - bioRxiv DO - 10.1101/2021.07.09.451843 SP - 2021.07.09.451843 AU - Rui Gong AU - Fangfang Jiang AU - Zane G. Moreland AU - Matthew J. Reynolds AU - Santiago Espinosa de los Reyes AU - Pinar S. Gurel AU - Arik Shams AU - Michael R. Bowl AU - Jonathan E. Bird AU - Gregory M. Alushin Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/07/12/2021.07.09.451843.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -