Loss of cargo binding in the human myosin VI deafness mutant R1166X leads to increased actin filament bindingReport as inadecuate


Loss of cargo binding in the human myosin VI deafness mutant R1166X leads to increased actin filament binding


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Publication Date: 2016-07-29

Journal Title: Biochemical Journal

Publisher: Portland Press

Volume: 473

Issue: 19

Number: 25

Pages: 3307-3319

Language: English

Type: Article

This Version: VoR

Metadata: Show full item record

Citation: Arden, S. D., Tumbarello, D. A., Butt, T., Kendrick-Jones, J., & Buss, F. (2016). Loss of cargo binding in the human myosin VI deafness mutant (R1166X) leads to increased actin filament binding. Biochemical Journal, 473 (19. 25), 3307-3319. https://doi.org/10.1042/BCJ20160571

Description: This is the final version of the article. It first appeared from from Portland Press via http://dx.doi.org/10.1042/BCJ20160571

Abstract: Mutations in myosin VI have been associated with autosomal-recessive (DFNB37) and autosomal-dominant (DFNA22) deafness in humans. Here, we characterise an myosin VI nonsense mutation (R1166X) that was identified in a family with hereditary hearing loss in Pakistan. This mutation leads to the deletion of the C-terminal 120 amino acids of the myosin VI cargo-binding domain, which includes the WWY-binding motif for the adaptor proteins LMTK2, Tom1 as well as Dab2. Interestingly, compromising myosin VI vesicle binding ability by expressing myosin VI with the R1166X mutation or with single point mutations in the adaptor-binding sites leads to increased F-actin binding of this myosin in vitro and in vivo. As our results highlight the importance of cargo attachment for regulating actin binding to the motor domain, we perform a detailed characterisation of adaptor protein binding and identify single amino acids within myosin VI required for binding to cargo adaptors. We not only show that the adaptor proteins can directly interact with the cargo-binding tail of myosin VI, but our in vitro studies also suggest that multiple adaptor proteins can bind simultaneously to non-overlapping sites in the myosin VI tail. In conclusion, our characterisation of the human myosin VI deafness mutant (R1166X) suggests that defects in cargo binding may leave myosin VI in a primed/activated state with an increased actin-binding ability.

Sponsorship: FB, SDA and DAT thank the Wellcome Trust for funding of a University Award to FB (086743), the CIMR Strategic Award (100140) and an equipment grant (093026). FB also thanks the Medical Research Council UK (MR/K000888/1) and the Biotechnology and Biological Sciences Research Council (BB/K00 1981/1) for funding of project grants. JKJ was supported by the Medical Research Council, UK (U105184323).

Embargo Lift Date: 2100-01-01

Identifiers:

External DOI: https://doi.org/10.1042/BCJ20160571

This record's URL: https://www.repository.cam.ac.uk/handle/1810/260331



Rights: Attribution 4.0 International

Licence URL: http://creativecommons.org/licenses/by/4.0





Author: Arden, Susan D.Tumbarello, David A.Butt, TariqKendrick-Jones, JohnBuss, Folma

Source: https://www.repository.cam.ac.uk/handle/1810/260331



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