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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/74919 |
| _version_ | 1828108419622502400 |
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| author | Maicon Landim-Vieira Matthew C Childers Amanda L Wacker Michelle Rodriquez Garcia Huan He Rakesh Singh Elizabeth A Brundage Jamie R Johnston Bryan A Whitson P Bryant Chase Paul ML Janssen Michael Regnier Brandon J Biesiadecki J Renato Pinto Michelle S Parvatiyar |
| author_facet | Maicon Landim-Vieira Matthew C Childers Amanda L Wacker Michelle Rodriquez Garcia Huan He Rakesh Singh Elizabeth A Brundage Jamie R Johnston Bryan A Whitson P Bryant Chase Paul ML Janssen Michael Regnier Brandon J Biesiadecki J Renato Pinto Michelle S Parvatiyar |
| author_sort | Maicon Landim-Vieira |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T10:46:31Z |
| format | Article |
| id | doaj.art-38e39ac9728c48009835c5d2747080b4 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:46:31Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-38e39ac9728c48009835c5d2747080b42022-12-22T04:29:03ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.74919Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human heartsMaicon Landim-Vieira0Matthew C Childers1https://orcid.org/0000-0003-2440-9612Amanda L Wacker2https://orcid.org/0000-0002-7580-7189Michelle Rodriquez Garcia3Huan He4Rakesh Singh5Elizabeth A Brundage6Jamie R Johnston7Bryan A Whitson8P Bryant Chase9https://orcid.org/0000-0001-9701-561XPaul ML Janssen10Michael Regnier11Brandon J Biesiadecki12J Renato Pinto13https://orcid.org/0000-0001-9092-4976Michelle S Parvatiyar14https://orcid.org/0000-0002-9416-0069Department of Biomedical Sciences, College of Medicine, The Florida State University, Tallahassee, United StatesDepartment of Bioengineering, College of Medicine, University of Washington, Seattle, United StatesDepartment of Nutrition and Integrative Physiology, The Florida State University, Tallahassee, United StatesDepartment of Biomedical Sciences, College of Medicine, The Florida State University, Tallahassee, United StatesDepartment of Biomedical Sciences, College of Medicine, The Florida State University, Tallahassee, United States; Translational Science Laboratory, College of Medicine, The Florida State University, Tallahassee, United StatesDepartment of Biomedical Sciences, College of Medicine, The Florida State University, Tallahassee, United States; Translational Science Laboratory, College of Medicine, The Florida State University, Tallahassee, United StatesDepartment of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, United StatesDepartment of Biomedical Sciences, College of Medicine, The Florida State University, Tallahassee, United StatesDepartment of Surgery, College of Medicine, The Ohio State University, Columbus, United StatesDepartment of Biological Science, The Florida State University, Tallahassee, United StatesDepartment of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, United StatesDepartment of Bioengineering, College of Medicine, University of Washington, Seattle, United StatesDepartment of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, United StatesDepartment of Biomedical Sciences, College of Medicine, The Florida State University, Tallahassee, United StatesDepartment of Nutrition and Integrative Physiology, The Florida State University, Tallahassee, United StatesPhosphorylation 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.https://elifesciences.org/articles/74919myosin heavy chainpost-translational modificationsheart failurehuman |
| spellingShingle | Maicon Landim-Vieira Matthew C Childers Amanda L Wacker Michelle Rodriquez Garcia Huan He Rakesh Singh Elizabeth A Brundage Jamie R Johnston Bryan A Whitson P Bryant Chase Paul ML Janssen Michael Regnier Brandon J Biesiadecki J Renato Pinto Michelle S Parvatiyar Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts eLife myosin heavy chain post-translational modifications heart failure human |
| 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 | myosin heavy chain post-translational modifications heart failure human |
| url | https://elifesciences.org/articles/74919 |
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