Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and non-ischemic human hearts
- Florida State University, United States
- University of Washington, United States
- The Ohio State University, United States
- Ohio State University, United States
Abstract
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 beta-myosin heavy chain (b-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 non-ischemic failing hearts compared to non-diseased hearts. Molecular dynamics 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 heart failure hearts.
Data availability
All data generated or analyzed during this study are included in the manuscript and the supporting files have been provided for Figures 2, 3, 7, 8 , 9 and Supplemental Figure 1, 2, 4, Tables 1, 2, 3 and 4.Mass spec data have been deposited at Dryad under the unique identifier DOI (doi:10.5061/dryad.s4mw6m97g).
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Data from: Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and non-ischemic human heartsDryad Digital Repository, doi:10.5061/dryad.s4mw6m97g.
Article and author information
Author details
Matthew C Childers
Michelle S Parvatiyar
Funding
American Heart Association (16SDG2912000)
- Michelle S Parvatiyar
Florida State University (46259)
- Michelle S Parvatiyar
National Institutes of Health (HL128683)
- Jose R Pinto
American Heart Association (2021AHAPRE216237)
- Maicon Landim-Vieira
National Science Foundation (ACI-1548562)
- Michael Regnier
National Institutes of Health (T32HL007828)
- Matthew C Childers
National Institutes of Health (P30AR074990)
- Michael Regnier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: This study was conducted with the highest ethical standards, human heart samples were collected and stored with full consent of parties involved and were provided by the Lifeline of Ohio with coordination from surgeons and transplant coordinators at the Ohio State University Wexner Medical Center. All aspects of this study were approved and conform to the ethical guidelines established by the Institutional Review Board of The Ohio State University under protocol #2012H0197.
Copyright
© 2022, Landim-Vieira et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and non-ischemic human hearts
eLife 11:e74919.
https://doi.org/10.7554/eLife.74919
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