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Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy

Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energeti...

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Autores principales: Viswanathan, Meera C., Schmidt, William, Rynkiewicz, Michael J., Agarwal, Karuna, Gao, Jian, Katz, Joseph, Lehman, William, Cammarato, Anthony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902318/
https://www.ncbi.nlm.nih.gov/pubmed/28903042
http://dx.doi.org/10.1016/j.celrep.2017.08.070
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author Viswanathan, Meera C.
Schmidt, William
Rynkiewicz, Michael J.
Agarwal, Karuna
Gao, Jian
Katz, Joseph
Lehman, William
Cammarato, Anthony
author_facet Viswanathan, Meera C.
Schmidt, William
Rynkiewicz, Michael J.
Agarwal, Karuna
Gao, Jian
Katz, Joseph
Lehman, William
Cammarato, Anthony
author_sort Viswanathan, Meera C.
collection PubMed
description Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energetically favorable F-actin-tropomyosin configuration, with tropomyosin positioned in a location that impedes actomyosin associations and promotes relaxation. Here, we provide data that directly support a vital role for these actin residues, termed the A-triad, in tropomyosin positioning in intact functioning muscle. By examining the effects of an A295S α-cardiac actin hypertrophic cardiomyopathy-causing mutation, over a range of increasingly complex in silico, in vitro, and in vivo Drosophila muscle models, we propose that subtle A-triad-tropomyosin perturbation can destabilize thin filament regulation, which leads to hypercontractility and triggers disease. Our efforts increase understanding of basic thin filament biology and help unravel the mechanistic basis of a complex cardiac disorder.
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spelling pubmed-59023182018-04-16 Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy Viswanathan, Meera C. Schmidt, William Rynkiewicz, Michael J. Agarwal, Karuna Gao, Jian Katz, Joseph Lehman, William Cammarato, Anthony Cell Rep Article Striated muscle contraction is regulated by the movement of tropomyosin over the thin filament surface, which blocks or exposes myosin binding sites on actin. Findings suggest that electrostatic contacts, particularly those between K326, K328, and R147 on actin and tropomyosin, establish an energetically favorable F-actin-tropomyosin configuration, with tropomyosin positioned in a location that impedes actomyosin associations and promotes relaxation. Here, we provide data that directly support a vital role for these actin residues, termed the A-triad, in tropomyosin positioning in intact functioning muscle. By examining the effects of an A295S α-cardiac actin hypertrophic cardiomyopathy-causing mutation, over a range of increasingly complex in silico, in vitro, and in vivo Drosophila muscle models, we propose that subtle A-triad-tropomyosin perturbation can destabilize thin filament regulation, which leads to hypercontractility and triggers disease. Our efforts increase understanding of basic thin filament biology and help unravel the mechanistic basis of a complex cardiac disorder. 2017-09-12 /pmc/articles/PMC5902318/ /pubmed/28903042 http://dx.doi.org/10.1016/j.celrep.2017.08.070 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Viswanathan, Meera C.
Schmidt, William
Rynkiewicz, Michael J.
Agarwal, Karuna
Gao, Jian
Katz, Joseph
Lehman, William
Cammarato, Anthony
Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy
title Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy
title_full Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy
title_fullStr Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy
title_full_unstemmed Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy
title_short Distortion of the Actin A-Triad Results in Contractile Disinhibition and Cardiomyopathy
title_sort distortion of the actin a-triad results in contractile disinhibition and cardiomyopathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902318/
https://www.ncbi.nlm.nih.gov/pubmed/28903042
http://dx.doi.org/10.1016/j.celrep.2017.08.070
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