Journal article
Allele-specific Effects of Human Deafness γ-Actin Mutations (DFNA20/26) on the Actin/Cofilin Interaction
The Journal of biological chemistry, Vol.284(27), pp.18260-18269
07/03/2009
DOI: 10.1074/jbc.M109.015818
PMCID: PMC2709362
PMID: 19419963
Abstract
Auditory hair cell function requires proper assembly and regulation of the nonmuscle gamma isoactin-rich cytoskeleton, and six point mutations in this isoactin cause a type of delayed onset autosomal dominant nonsyndromic progressive hearing loss, DFNA20/26. The molecular basis underlying this actin-dependent hearing loss is unknown. To address this problem, the mutations have been introduced into yeast actin, and their effects on actin function were assessed
in vivo
and
in vitro
. Because we previously showed that polymerization was unaffected in five of the six mutants, we have focused on proteins that regulate actin, in particular cofilin, which severs F-actin and sequesters actin monomers. The mutations do not affect the interaction of cofilin with G-actin. However, T89I and V370A mutant F-actins are much more susceptible to cofilin disassembly than WT filaments
in vitro
. Conversely, P332A filaments demonstrate enhanced resistance. Wild type actin solutions containing T89I, K118M, or P332A mutant actins at mole fractions similar to those found in the hair cell respond
in vitro
toward cofilin in a manner proportional to the level of the mutant present. Finally, depression of cofilin action
in vivo
by elimination of the cofilin-activating protein, Aip1p, rescues the inability to grow on glycerol caused by K118M, T278I, P332A, and V370A. These results suggest that a filament instability caused by these mutations can be balanced by decreasing a system
in vivo
that promotes increased filament turnover. Such mutant-dependent filament destabilization could easily result in hair cell malfunction leading to the late-onset hearing loss observed in these patients.
Details
- Title: Subtitle
- Allele-specific Effects of Human Deafness γ-Actin Mutations (DFNA20/26) on the Actin/Cofilin Interaction
- Creators
- Keith E Bryan - From the Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1109Peter A Rubenstein - From the Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242-1109
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.284(27), pp.18260-18269
- DOI
- 10.1074/jbc.M109.015818
- PMID
- 19419963
- PMCID
- PMC2709362
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
- Grant note
- DC008803 / National Institutes of Health
- Language
- English
- Date published
- 07/03/2009
- Academic Unit
- Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984024519302771
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