Two Deafness-Causing Actin Mutations (DFNA20/26) Have Allosteric Effects on the Actin Structure

Lauren Jepsen; Karina A Kruth; Peter A Rubenstein; David Sept

doi:10.1016/j.bpj.2016.06.012

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Two Deafness-Causing Actin Mutations (DFNA20/26) Have Allosteric Effects on the Actin Structure

Journal article

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Two Deafness-Causing Actin Mutations (DFNA20/26) Have Allosteric Effects on the Actin Structure

Lauren Jepsen, Karina A Kruth, Peter A Rubenstein and David Sept

Biophysical journal, Vol.111(2), pp.323-332

07/26/2016

DOI: 10.1016/j.bpj.2016.06.012

PMCID: PMC4968419

PMID: 27463135

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Abstract

Point mutations in γ-cytoplasmic actin have been shown to result in autosomal-dominant, nonsyndromic, early-onset deafness. Two mutations at the same site, K118M and K118N, provide a unique opportunity to compare the effects of two dissimilar amino acid substitutions that produce a similar phenotype in humans. K118 resides in a helix that runs from K113 to T126, and mutations that alter the position, dynamics, and/or biochemistry of this helix can result in a wide range of pathologies. Using a combination of computational and experimental studies, both employing yeast actin, we find that these mutations at K118 result in changes in the structure and dynamics of the DNase-I loop, alterations in the structure of the H73 loop as well as the side-chain orientations of W79 and W86, changes in nucleotide exchange rates, and significant shifts in the twist of the actin monomer. Interestingly, in the case of K118N, the twist of the monomer is nearly identical to that of the F-actin protomer, and in vitro polymerization assays show that this mutation results in faster polymerization. Taken together, these results indicate that mutations at this site give rise to a series of small changes that can be tolerated in vivo but result in misregulation of actin assembly and dynamics.

Point Mutation

Protein Conformation, alpha-Helical

Allosteric Regulation - genetics

Phosphates - metabolism

Deafness - genetics

Actins - metabolism

Actins - chemistry

Acrylamide - chemistry

Nucleotides - metabolism

Molecular Dynamics Simulation

Actins - genetics

Details

Title: Subtitle: Two Deafness-Causing Actin Mutations (DFNA20/26) Have Allosteric Effects on the Actin Structure
Creators: Lauren Jepsen - Bioinformatics Graduate Program, University of Michigan, Ann Arbor, Michigan; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
Karina A Kruth - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, Iowa
Peter A Rubenstein - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, Iowa
David Sept - Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. Electronic address: dsept@umich.edu
Resource Type: Journal article
Publication Details: Biophysical journal, Vol.111(2), pp.323-332
Publisher: United States
DOI: 10.1016/j.bpj.2016.06.012
PMID: 27463135
PMCID: PMC4968419
ISSN: 0006-3495
eISSN: 1542-0086
Grant note: R55 DC008803 / NIDCD NIH HHS R01 DC008803 / NIDCD NIH HHS
Language: English
Date published: 07/26/2016
Academic Unit: Psychiatry; Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984024400402771

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