Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation MYBPC3Δ25bp/D389V

Mutations in the gene encoding cardiac myosin-binding protein-C (MyBPC), a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function, are a common cause for the development of hypertrophic cardiomyopathy. About 10% of carriers of the Δ25bp variant of <i&g...

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Autores principales:	Frederic V. Schwäbe, Emanuel K. Peter, Manuel H. Taft, Dietmar J. Manstein
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	hypertrophic cardiomyopathy heart disorder MyBPC enhanced molecular dynamics simulations allosteric trigger cardiac contractility Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/e876ece9a57f4604ab6ccf0c98896ee4
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spelling	oai:doaj.org-article:e876ece9a57f4604ab6ccf0c98896ee42021-11-11T17:22:10ZAssessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>10.3390/ijms2221119491422-00671661-6596https://doaj.org/article/e876ece9a57f4604ab6ccf0c98896ee42021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11949https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Mutations in the gene encoding cardiac myosin-binding protein-C (MyBPC), a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function, are a common cause for the development of hypertrophic cardiomyopathy. About 10% of carriers of the Δ25bp variant of <i>MYBPC3</i>, which is common in individuals from South Asia, are also carriers of the D389V variant on the same allele. Compared with noncarriers and those with <i>MYBPC3</i><sup>Δ<i>25bp</i></sup> alone, indicators for the development of hypertrophic cardiomyopathy occur with increased frequency in <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup> carriers. Residue D389 lies in the IgI-like C2 domain that is part of the N-terminal region of MyBPC. To probe the effects of mutation D389V on structure, thermostability, and protein–protein interactions, we produced and characterized wild-type and mutant constructs corresponding to the isolated 10 kDa C2 domain and a 52 kDa N-terminal fragment that includes subdomains C0 to C2. Our results show marked reductions in the melting temperatures of D389V mutant constructs. Interactions of construct C0–C2 D389V with the cardiac isoforms of myosin-2 and actin remain unchanged. Molecular dynamics simulations reveal changes in the stiffness and conformer dynamics of domain C2 caused by mutation D389V. Our results suggest a pathomechanism for the development of HCM based on the toxic buildup of misfolded protein in young <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup> carriers that is supplanted and enhanced by C-zone haploinsufficiency at older ages.Frederic V. SchwäbeEmanuel K. PeterManuel H. TaftDietmar J. MansteinMDPI AGarticlehypertrophic cardiomyopathyheart disorderMyBPCenhanced molecular dynamics simulationsallosteric triggercardiac contractilityBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11949, p 11949 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	hypertrophic cardiomyopathy heart disorder MyBPC enhanced molecular dynamics simulations allosteric trigger cardiac contractility Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	hypertrophic cardiomyopathy heart disorder MyBPC enhanced molecular dynamics simulations allosteric trigger cardiac contractility Biology (General) QH301-705.5 Chemistry QD1-999 Frederic V. Schwäbe Emanuel K. Peter Manuel H. Taft Dietmar J. Manstein Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>
description	Mutations in the gene encoding cardiac myosin-binding protein-C (MyBPC), a thick filament assembly protein that stabilizes sarcomeric structure and regulates cardiac function, are a common cause for the development of hypertrophic cardiomyopathy. About 10% of carriers of the Δ25bp variant of <i>MYBPC3</i>, which is common in individuals from South Asia, are also carriers of the D389V variant on the same allele. Compared with noncarriers and those with <i>MYBPC3</i><sup>Δ<i>25bp</i></sup> alone, indicators for the development of hypertrophic cardiomyopathy occur with increased frequency in <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup> carriers. Residue D389 lies in the IgI-like C2 domain that is part of the N-terminal region of MyBPC. To probe the effects of mutation D389V on structure, thermostability, and protein–protein interactions, we produced and characterized wild-type and mutant constructs corresponding to the isolated 10 kDa C2 domain and a 52 kDa N-terminal fragment that includes subdomains C0 to C2. Our results show marked reductions in the melting temperatures of D389V mutant constructs. Interactions of construct C0–C2 D389V with the cardiac isoforms of myosin-2 and actin remain unchanged. Molecular dynamics simulations reveal changes in the stiffness and conformer dynamics of domain C2 caused by mutation D389V. Our results suggest a pathomechanism for the development of HCM based on the toxic buildup of misfolded protein in young <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup> carriers that is supplanted and enhanced by C-zone haploinsufficiency at older ages.
format	article
author	Frederic V. Schwäbe Emanuel K. Peter Manuel H. Taft Dietmar J. Manstein
author_facet	Frederic V. Schwäbe Emanuel K. Peter Manuel H. Taft Dietmar J. Manstein
author_sort	Frederic V. Schwäbe
title	Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>
title_short	Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>
title_full	Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>
title_fullStr	Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>
title_full_unstemmed	Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>
title_sort	assessment of the contribution of a thermodynamic and mechanical destabilization of myosin-binding protein c domain c2 to the pathomechanism of hypertrophic cardiomyopathy-causing double mutation <i>mybpc3</i><sup>δ<i>25bp/d389v</i></sup>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e876ece9a57f4604ab6ccf0c98896ee4
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Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double Mutation <i>MYBPC3</i><sup>Δ<i>25bp/D389V</i></sup>

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