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Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin

Cardiomyopathies are a major health problem, with inherited cardiomyopathies, many of which are caused by mutations in genes encoding sarcomeric proteins, constituting an ever-increasing fraction of cases. To begin to study the mechanisms by which these mutations cause disease, we have employed an i...

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Autores principales: Margaret Sunitha, S, Mercer, John A., Spudich, James A., Sowdhamini, Ramanathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Libertas Academica 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468436/
https://www.ncbi.nlm.nih.gov/pubmed/23071391
http://dx.doi.org/10.4137/BBI.S9798
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author Margaret Sunitha, S
Mercer, John A.
Spudich, James A.
Sowdhamini, Ramanathan
author_facet Margaret Sunitha, S
Mercer, John A.
Spudich, James A.
Sowdhamini, Ramanathan
author_sort Margaret Sunitha, S
collection PubMed
description Cardiomyopathies are a major health problem, with inherited cardiomyopathies, many of which are caused by mutations in genes encoding sarcomeric proteins, constituting an ever-increasing fraction of cases. To begin to study the mechanisms by which these mutations cause disease, we have employed an integrative modelling approach to study the interactions between tropomyosin and actin. Starting from the existing blocked state model, we identified a specific zone on the actin surface which is highly favourable to support tropomyosin sliding from the blocked/closed states to the open state. We then analysed the predicted actin-tropomyosin interface regions for the three states. Each quasi-repeat of tropomyosin was studied for its interaction strength and evolutionary conservation to focus on smaller surface zones. Finally, we show that the distribution of the known cardiomyopathy mutations of α-tropomyosin is consistent with our model. This analysis provides structural insights into the possible mode of interactions between tropomyosin and actin in the open state for the first time.
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spelling pubmed-34684362012-10-15 Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin Margaret Sunitha, S Mercer, John A. Spudich, James A. Sowdhamini, Ramanathan Bioinform Biol Insights Original Research Cardiomyopathies are a major health problem, with inherited cardiomyopathies, many of which are caused by mutations in genes encoding sarcomeric proteins, constituting an ever-increasing fraction of cases. To begin to study the mechanisms by which these mutations cause disease, we have employed an integrative modelling approach to study the interactions between tropomyosin and actin. Starting from the existing blocked state model, we identified a specific zone on the actin surface which is highly favourable to support tropomyosin sliding from the blocked/closed states to the open state. We then analysed the predicted actin-tropomyosin interface regions for the three states. Each quasi-repeat of tropomyosin was studied for its interaction strength and evolutionary conservation to focus on smaller surface zones. Finally, we show that the distribution of the known cardiomyopathy mutations of α-tropomyosin is consistent with our model. This analysis provides structural insights into the possible mode of interactions between tropomyosin and actin in the open state for the first time. Libertas Academica 2012-10-03 /pmc/articles/PMC3468436/ /pubmed/23071391 http://dx.doi.org/10.4137/BBI.S9798 Text en © 2012 the author(s), publisher and licensee Libertas Academica Ltd. This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
spellingShingle Original Research
Margaret Sunitha, S
Mercer, John A.
Spudich, James A.
Sowdhamini, Ramanathan
Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin
title Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin
title_full Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin
title_fullStr Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin
title_full_unstemmed Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin
title_short Integrative Structural Modelling of the Cardiac Thin Filament: Energetics at the Interface and Conservation Patterns Reveal a Spotlight on Period 2 of Tropomyosin
title_sort integrative structural modelling of the cardiac thin filament: energetics at the interface and conservation patterns reveal a spotlight on period 2 of tropomyosin
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468436/
https://www.ncbi.nlm.nih.gov/pubmed/23071391
http://dx.doi.org/10.4137/BBI.S9798
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