Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease

Abstract Coordinated sarcomere proteins produce contraction force for muscle shortening. In human ventriculum they include the cardiac myosin motor (βmys), repetitively converting ATP free energy into work, and myosin binding protein C (MYBPC3) that in complex with βmys is regulatory. Single nucleot...

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Autor principal:	Thomas P. Burghardt
Formato:	article
Lenguaje:	EN
Publicado:	Springer 2021
Materias:	Single nucleotide variants Cardiac muscle inheritable disease 2D Correlation genetics Interprotein coordinated domains Serial founder effect Population genetic divergence proxy Medicine R
Acceso en línea:	https://doaj.org/article/40cc9693b4064125aff67ab9a117cf45
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spelling	oai:doaj.org-article:40cc9693b4064125aff67ab9a117cf452021-11-21T12:03:46ZNatural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease10.1186/s43556-021-00056-x2662-8651https://doaj.org/article/40cc9693b4064125aff67ab9a117cf452021-11-01T00:00:00Zhttps://doi.org/10.1186/s43556-021-00056-xhttps://doaj.org/toc/2662-8651Abstract Coordinated sarcomere proteins produce contraction force for muscle shortening. In human ventriculum they include the cardiac myosin motor (βmys), repetitively converting ATP free energy into work, and myosin binding protein C (MYBPC3) that in complex with βmys is regulatory. Single nucleotide variants (SNVs) causing hereditary heart diseases frequently target this protein pair. The βmys/MYBPC3 complex models a regulated motor and is used here to study how the proteins couple. SNVs in βmys or MYBPC3 survey human populations worldwide. Their protein expression modifies domain structure affecting phenotype and pathogenicity outcomes. When the SNV modified domain locates to inter-protein contacts it could affect complex coordination. Domains involved, one in βmys the other in MYBPC3, form coordinated domains (co-domains). Co-domain bilateral structure implies the possibility for a shared impact from SNV modification in either domain suggesting a correlated response to a common perturbation could identify their location. Genetic divergence over human populations is proposed to perturb SNV probability coupling that is detected by cross-correlation in 2D correlation genetics (2D-CG). SNV probability data and 2D-CG identify three critical sites, two in MYBPC3 with links to several domains across the βmys motor, and, one in βmys with links to the MYBPC3 regulatory domain. MYBPC3 sites are hinges sterically enabling regulatory interactions with βmys. The βmys site is the actin binding C-loop (residues 359-377). The C-loop is a trigger for actin-activated myosin ATPase and a contraction velocity modulator. Co-domain identification implies their spatial proximity suggesting a novel approach for in vivo protein complex structure determination.Thomas P. BurghardtSpringerarticleSingle nucleotide variantsCardiac muscle inheritable disease2D Correlation geneticsInterprotein coordinated domainsSerial founder effectPopulation genetic divergence proxyMedicineRENMolecular Biomedicine, Vol 2, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Single nucleotide variants Cardiac muscle inheritable disease 2D Correlation genetics Interprotein coordinated domains Serial founder effect Population genetic divergence proxy Medicine R
spellingShingle	Single nucleotide variants Cardiac muscle inheritable disease 2D Correlation genetics Interprotein coordinated domains Serial founder effect Population genetic divergence proxy Medicine R Thomas P. Burghardt Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease
description	Abstract Coordinated sarcomere proteins produce contraction force for muscle shortening. In human ventriculum they include the cardiac myosin motor (βmys), repetitively converting ATP free energy into work, and myosin binding protein C (MYBPC3) that in complex with βmys is regulatory. Single nucleotide variants (SNVs) causing hereditary heart diseases frequently target this protein pair. The βmys/MYBPC3 complex models a regulated motor and is used here to study how the proteins couple. SNVs in βmys or MYBPC3 survey human populations worldwide. Their protein expression modifies domain structure affecting phenotype and pathogenicity outcomes. When the SNV modified domain locates to inter-protein contacts it could affect complex coordination. Domains involved, one in βmys the other in MYBPC3, form coordinated domains (co-domains). Co-domain bilateral structure implies the possibility for a shared impact from SNV modification in either domain suggesting a correlated response to a common perturbation could identify their location. Genetic divergence over human populations is proposed to perturb SNV probability coupling that is detected by cross-correlation in 2D correlation genetics (2D-CG). SNV probability data and 2D-CG identify three critical sites, two in MYBPC3 with links to several domains across the βmys motor, and, one in βmys with links to the MYBPC3 regulatory domain. MYBPC3 sites are hinges sterically enabling regulatory interactions with βmys. The βmys site is the actin binding C-loop (residues 359-377). The C-loop is a trigger for actin-activated myosin ATPase and a contraction velocity modulator. Co-domain identification implies their spatial proximity suggesting a novel approach for in vivo protein complex structure determination.
format	article
author	Thomas P. Burghardt
author_facet	Thomas P. Burghardt
author_sort	Thomas P. Burghardt
title	Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease
title_short	Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease
title_full	Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease
title_fullStr	Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease
title_full_unstemmed	Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease
title_sort	natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease
publisher	Springer
publishDate	2021
url	https://doaj.org/article/40cc9693b4064125aff67ab9a117cf45
work_keys_str_mv	AT thomaspburghardt naturalvariantfrequenciesacrossdomainsfromdifferentsarcomereproteinscrosscorrelatetoidentifyinterproteincontactsassociatedwithcardiacmusclefunctionanddisease
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Natural variant frequencies across domains from different sarcomere proteins cross-correlate to identify inter-protein contacts associated with cardiac muscle function and disease

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