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Distinct effects of two hearing loss-associated mutations in the sarcomeric myosin MYH7b

Lee, Lindsey A., Barrick, Samantha K., Buvoli, Ada E., Walklate, Jonathan, Stump, W. Tom, Geeves, Michael A., Greenberg, Michael J., Leinwand, Leslie A. (2023) Distinct effects of two hearing loss-associated mutations in the sarcomeric myosin MYH7b. Journal of Biological Chemistry, 299 (5). Article Number 104631. ISSN 0021-9258. (doi:10.1016/j.jbc.2023.104631) (KAR id:101024)

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https://doi.org/10.1016/j.jbc.2023.104631

Abstract

For decades, sarcomeric myosin heavy chain proteins were assumed to be restricted to striated muscle where they function as molecular motors that contract muscle. However, MYH7b, an evolutionarily ancient member of this myosin family, has been detected in mammalian nonmuscle tissues, and mutations in MYH7b are linked to hereditary hearing loss in compound heterozygous patients. These mutations are the first associated with hearing loss rather than a muscle pathology, and because there are no homologous mutations in other myosin isoforms, their functional effects were unknown. We generated recombinant human MYH7b harboring the D515N or R1651Q hearing loss-associated mutation and studied their effects on motor activity and structural and assembly properties, respectively. The D515N mutation had no effect on steady-state actin-activated ATPase rate or load-dependent detachment kinetics, but increased actin sliding velocity due to an increased displacement during the myosin working stroke. Furthermore, we found that the D515N mutation caused an increase in the proportion of myosin heads that occupy the disordered-relaxed state, meaning more myosin heads are available to interact with actin. Although we found no impact of the R1651Q mutation on myosin rod secondary structure or solubility, we observed a striking aggregation phenotype when this mutation was introduced into nonmuscle cells. Our results suggest that each mutation independently affects MYH7b function and structure. Together, these results provide the foundation for further study of a role for MYH7b outside of the sarcomere.

Item Type: Article
DOI/Identification number: 10.1016/j.jbc.2023.104631
Uncontrolled keywords: Molecular motor, myosin, actin, kinetics, SRX (super-relaxed state), myopathy, coiled-coil
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Funders: National Institutes of Health (https://ror.org/01cwqze88)
Depositing User: Michael Geeves
Date Deposited: 21 Apr 2023 14:17 UTC
Last Modified: 24 Apr 2023 10:13 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/101024 (The current URI for this page, for reference purposes)

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