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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
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.
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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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