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Modeling Human Cardiac Thin Filament Structures
Striated muscle contraction is regulated in a calcium-dependent manner through dynamic motions of the tropomyosin/troponin polymer, a multicomponent complex wrapped around actin-containing thin filaments. Tropomyosin/troponin sterically blocks myosin-binding at low-calcium concentrations but moves t...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257132/ https://www.ncbi.nlm.nih.gov/pubmed/35812320 http://dx.doi.org/10.3389/fphys.2022.932333 |
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author | Rynkiewicz, Michael J. Pavadai, Elumalai Lehman, William |
author_facet | Rynkiewicz, Michael J. Pavadai, Elumalai Lehman, William |
author_sort | Rynkiewicz, Michael J. |
collection | PubMed |
description | Striated muscle contraction is regulated in a calcium-dependent manner through dynamic motions of the tropomyosin/troponin polymer, a multicomponent complex wrapped around actin-containing thin filaments. Tropomyosin/troponin sterically blocks myosin-binding at low-calcium concentrations but moves to expose myosin-binding sites at high-calcium concentrations leading to force development. Understanding the key intermolecular interactions that define these dynamic motions will promote our understanding of mutation-induced contractile dysfunction that eventually leads to hypertrophic cardiomyopathy, dilated cardiomyopathy, and skeletal myopathies. Advancements in cryoelectron microscopy (cryoEM) have resulted in a partial elucidation of structures of the thin filament, revealing many atomic-level interactions between the component proteins and critical calcium-dependent conformational alterations. However, building models at the resolutions achieved can be challenging since landmarks in the maps are often missing or ambiguous. Therefore, current computational analyses including de novo structure prediction, protein-protein docking, molecular dynamics flexible fitting, and molecular dynamics simulations are needed to ensure good quality models. We review here our efforts to model the troponin T domain spanning the head-to-tail overlap domain of tropomyosin, improving previous models. Next, we refined the published cryoEM modeled structures, which had mistakenly compressed alpha helices, with a model that has expected helical parameters while matching densities in the cryoEM volume. Lastly, we used this model to reinterpret the interactions between tropomyosin and troponin I showing key features that hold the tropomyosin cable in its low-calcium, sterically blocking position. These revised thin filament models show improved intermolecular interactions in the key low- and high-calcium regulatory states, providing novel insights into function. |
format | Online Article Text |
id | pubmed-9257132 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92571322022-07-07 Modeling Human Cardiac Thin Filament Structures Rynkiewicz, Michael J. Pavadai, Elumalai Lehman, William Front Physiol Physiology Striated muscle contraction is regulated in a calcium-dependent manner through dynamic motions of the tropomyosin/troponin polymer, a multicomponent complex wrapped around actin-containing thin filaments. Tropomyosin/troponin sterically blocks myosin-binding at low-calcium concentrations but moves to expose myosin-binding sites at high-calcium concentrations leading to force development. Understanding the key intermolecular interactions that define these dynamic motions will promote our understanding of mutation-induced contractile dysfunction that eventually leads to hypertrophic cardiomyopathy, dilated cardiomyopathy, and skeletal myopathies. Advancements in cryoelectron microscopy (cryoEM) have resulted in a partial elucidation of structures of the thin filament, revealing many atomic-level interactions between the component proteins and critical calcium-dependent conformational alterations. However, building models at the resolutions achieved can be challenging since landmarks in the maps are often missing or ambiguous. Therefore, current computational analyses including de novo structure prediction, protein-protein docking, molecular dynamics flexible fitting, and molecular dynamics simulations are needed to ensure good quality models. We review here our efforts to model the troponin T domain spanning the head-to-tail overlap domain of tropomyosin, improving previous models. Next, we refined the published cryoEM modeled structures, which had mistakenly compressed alpha helices, with a model that has expected helical parameters while matching densities in the cryoEM volume. Lastly, we used this model to reinterpret the interactions between tropomyosin and troponin I showing key features that hold the tropomyosin cable in its low-calcium, sterically blocking position. These revised thin filament models show improved intermolecular interactions in the key low- and high-calcium regulatory states, providing novel insights into function. Frontiers Media S.A. 2022-06-22 /pmc/articles/PMC9257132/ /pubmed/35812320 http://dx.doi.org/10.3389/fphys.2022.932333 Text en Copyright © 2022 Rynkiewicz, Pavadai and Lehman. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Rynkiewicz, Michael J. Pavadai, Elumalai Lehman, William Modeling Human Cardiac Thin Filament Structures |
title | Modeling Human Cardiac Thin Filament Structures |
title_full | Modeling Human Cardiac Thin Filament Structures |
title_fullStr | Modeling Human Cardiac Thin Filament Structures |
title_full_unstemmed | Modeling Human Cardiac Thin Filament Structures |
title_short | Modeling Human Cardiac Thin Filament Structures |
title_sort | modeling human cardiac thin filament structures |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257132/ https://www.ncbi.nlm.nih.gov/pubmed/35812320 http://dx.doi.org/10.3389/fphys.2022.932333 |
work_keys_str_mv | AT rynkiewiczmichaelj modelinghumancardiacthinfilamentstructures AT pavadaielumalai modelinghumancardiacthinfilamentstructures AT lehmanwilliam modelinghumancardiacthinfilamentstructures |