Gong, Rui;
Jiang, Fangfang;
Moreland, Zane G;
Reynolds, Matthew J;
de los Reyes, Santiago Espinosa;
Gurel, Pinar;
Shams, Arik;
... Alushin, Gregory M; + view all
(2022)
Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia.
Science Advances
, 8
(29)
10.1126/sciadv.abl4733.
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Abstract
The motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and mutations in myosin-15 cause hereditary deafness. In addition to transporting actin regulatory machinery to stereocilia tips, myosin-15 directly nucleates actin filament (“F-actin”) assembly, which is disrupted by a progressive hearing loss mutation (p.D1647G, “jordan”). Here, we present cryo–electron microscopy structures of myosin-15 bound to F-actin, providing a framework for interpreting the impacts of deafness mutations on motor activity and actin nucleation. 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. Adenosine diphosphate–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.
| Type: | Article |
|---|---|
| Title: | Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/sciadv.abl4733 |
| Publisher version: | https://doi.org/10.1126/sciadv.abl4733 |
| Language: | English |
| Additional information: | © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > The Ear Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10152541 |
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