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Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts
Phosphorylation and acetylation of sarcomeric proteins are important for fine-tuning myocardial contractility. Here, we used bottom-up proteomics and label-free quantification to identify novel post-translational modifications (PTMs) on β-myosin heavy chain (β-MHC) in normal and failing human heart...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122498/ https://www.ncbi.nlm.nih.gov/pubmed/35502901 http://dx.doi.org/10.7554/eLife.74919 |
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author | Landim-Vieira, Maicon Childers, Matthew C Wacker, Amanda L Garcia, Michelle Rodriquez He, Huan Singh, Rakesh Brundage, Elizabeth A Johnston, Jamie R Whitson, Bryan A Chase, P Bryant Janssen, Paul ML Regnier, Michael Biesiadecki, Brandon J Pinto, J Renato Parvatiyar, Michelle S |
author_facet | Landim-Vieira, Maicon Childers, Matthew C Wacker, Amanda L Garcia, Michelle Rodriquez He, Huan Singh, Rakesh Brundage, Elizabeth A Johnston, Jamie R Whitson, Bryan A Chase, P Bryant Janssen, Paul ML Regnier, Michael Biesiadecki, Brandon J Pinto, J Renato Parvatiyar, Michelle S |
author_sort | Landim-Vieira, Maicon |
collection | PubMed |
description | Phosphorylation and acetylation of sarcomeric proteins are important for fine-tuning myocardial contractility. Here, we used bottom-up proteomics and label-free quantification to identify novel post-translational modifications (PTMs) on β-myosin heavy chain (β-MHC) in normal and failing human heart tissues. We report six acetylated lysines and two phosphorylated residues: K34-Ac, K58-Ac, S210-P, K213-Ac, T215-P, K429-Ac, K951-Ac, and K1195-Ac. K951-Ac was significantly reduced in both ischemic and nonischemic failing hearts compared to nondiseased hearts. Molecular dynamics (MD) simulations show that K951-Ac may impact stability of thick filament tail interactions and ultimately myosin head positioning. K58-Ac altered the solvent-exposed SH3 domain surface – known for protein–protein interactions – but did not appreciably change motor domain conformation or dynamics under conditions studied. Together, K213-Ac/T215-P altered loop 1’s structure and dynamics – known to regulate ADP-release, ATPase activity, and sliding velocity. Our study suggests that β-MHC acetylation levels may be influenced more by the PTM location than the type of heart disease since less protected acetylation sites are reduced in both heart failure groups. Additionally, these PTMs have potential to modulate interactions between β-MHC and other regulatory sarcomeric proteins, ADP-release rate of myosin, flexibility of the S2 region, and cardiac myofilament contractility in normal and failing hearts. |
format | Online Article Text |
id | pubmed-9122498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-91224982022-05-21 Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts Landim-Vieira, Maicon Childers, Matthew C Wacker, Amanda L Garcia, Michelle Rodriquez He, Huan Singh, Rakesh Brundage, Elizabeth A Johnston, Jamie R Whitson, Bryan A Chase, P Bryant Janssen, Paul ML Regnier, Michael Biesiadecki, Brandon J Pinto, J Renato Parvatiyar, Michelle S eLife Structural Biology and Molecular Biophysics Phosphorylation and acetylation of sarcomeric proteins are important for fine-tuning myocardial contractility. Here, we used bottom-up proteomics and label-free quantification to identify novel post-translational modifications (PTMs) on β-myosin heavy chain (β-MHC) in normal and failing human heart tissues. We report six acetylated lysines and two phosphorylated residues: K34-Ac, K58-Ac, S210-P, K213-Ac, T215-P, K429-Ac, K951-Ac, and K1195-Ac. K951-Ac was significantly reduced in both ischemic and nonischemic failing hearts compared to nondiseased hearts. Molecular dynamics (MD) simulations show that K951-Ac may impact stability of thick filament tail interactions and ultimately myosin head positioning. K58-Ac altered the solvent-exposed SH3 domain surface – known for protein–protein interactions – but did not appreciably change motor domain conformation or dynamics under conditions studied. Together, K213-Ac/T215-P altered loop 1’s structure and dynamics – known to regulate ADP-release, ATPase activity, and sliding velocity. Our study suggests that β-MHC acetylation levels may be influenced more by the PTM location than the type of heart disease since less protected acetylation sites are reduced in both heart failure groups. Additionally, these PTMs have potential to modulate interactions between β-MHC and other regulatory sarcomeric proteins, ADP-release rate of myosin, flexibility of the S2 region, and cardiac myofilament contractility in normal and failing hearts. eLife Sciences Publications, Ltd 2022-05-03 /pmc/articles/PMC9122498/ /pubmed/35502901 http://dx.doi.org/10.7554/eLife.74919 Text en © 2022, Landim-Vieira et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Structural Biology and Molecular Biophysics Landim-Vieira, Maicon Childers, Matthew C Wacker, Amanda L Garcia, Michelle Rodriquez He, Huan Singh, Rakesh Brundage, Elizabeth A Johnston, Jamie R Whitson, Bryan A Chase, P Bryant Janssen, Paul ML Regnier, Michael Biesiadecki, Brandon J Pinto, J Renato Parvatiyar, Michelle S Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts |
title | Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts |
title_full | Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts |
title_fullStr | Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts |
title_full_unstemmed | Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts |
title_short | Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts |
title_sort | post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts |
topic | Structural Biology and Molecular Biophysics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122498/ https://www.ncbi.nlm.nih.gov/pubmed/35502901 http://dx.doi.org/10.7554/eLife.74919 |
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