Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

Sarah E Bergeron; Elesa W Wedemeyer; Rose Lee; Kuo-Kuang Wen; Melissa McKane; Alyson R Pierick; Anthony P Berger; Peter A Rubenstein; Heather L Bartlett

doi:10.1074/jbc.M110.203174

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Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

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Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function

Sarah E Bergeron, Elesa W Wedemeyer, Rose Lee, Kuo-Kuang Wen, Melissa McKane, Alyson R Pierick, Anthony P Berger, Peter A Rubenstein and Heather L Bartlett

The Journal of biological chemistry, Vol.286(13), pp.11356-11369

04/01/2011

DOI: 10.1074/jbc.M110.203174

PMCID: PMC3064192

PMID: 21288906

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Abstract

Twenty-two missense mutations in ACTA2 , which encodes α-smooth muscle actin, have been identified to cause thoracic aortic aneurysm and dissection. Limited access to diseased tissue, the presence of multiple unresolvable actin isoforms in the cell, and lack of an animal model have prevented analysis of the biochemical mechanisms underlying this pathology. We have utilized actin from the yeast Saccharomyces cerevisiae , 86% identical to human α-smooth muscle actin, as a model. Two of the known human mutations, N115T and R116Q, were engineered into yeast actin, and their effect on actin function in vivo and in vitro was investigated. Both mutants exhibited reduced ability to grow under a variety of stress conditions, which hampered N115T cells more than R116Q cells. Both strains exhibited abnormal mitochondrial morphology indicative of a faulty actin cytoskeleton. In vitro , the mutant actins exhibited altered thermostability and nucleotide exchange rates, indicating effects of the mutations on monomer conformation, with R116Q the most severely affected. N115T demonstrated a biphasic elongation phase during polymerization, whereas R116Q demonstrated a markedly extended nucleation phase. Allele-specific effects were also seen on critical concentration, rate of depolymerization, and filament treadmilling. R116Q filaments were hypersensitive to severing by the actin-binding protein cofilin. In contrast, N115T filaments were hyposensitive to cofilin despite nearly normal binding affinities of actin for cofilin. The mutant-specific effects on actin behavior suggest that individual mechanisms may contribute to thoracic aortic aneurysm and dissection.

Cytoskeleton

Protein Structure and Folding

Yeast

Actin

Microfilaments

TAAD

Aneurysm

Smooth Muscle

Thoracic Aortic Aneurysm and Dissection

Details

Title: Subtitle: Allele-specific Effects of Thoracic Aortic Aneurysm and Dissection α-Smooth Muscle Actin Mutations on Actin Function
Creators: Sarah E Bergeron - From the
Elesa W Wedemeyer - Department of Pediatrics, Roy A. and Lucille A. Carver College of Medicine, and
Rose Lee - From the
Kuo-Kuang Wen - From the
Melissa McKane - From the
Alyson R Pierick - From the
Anthony P Berger - From the
Peter A Rubenstein - From the
Heather L Bartlett - From the
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.286(13), pp.11356-11369
DOI: 10.1074/jbc.M110.203174
PMID: 21288906
PMCID: PMC3064192
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; UL1RR024979 / National Institutes of Health
Alternative title: Effects of α-Smooth Muscle Actin Mutations on Actin Function
Language: English
Date published: 04/01/2011
Academic Unit: Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984025260002771

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