Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and nonischemic human hearts
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Evaluation Summary:
This study reports new post-translational modifications (PTMs) to β-myosin heavy chain, using tissue samples from normal and failing human hearts. Atomistic simulations of myosin molecular dynamics suggest that these PTMs lead to meaningful alterations in structure, solvent exposure, and dynamics of certain regions of the protein. These data and simulations provide a foundation for further work to determine the precise functional significance of β-myosin heavy chain PTMs. The work will be of interest to cell biologists and cardiologists.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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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 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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Evaluation Summary:
This study reports new post-translational modifications (PTMs) to β-myosin heavy chain, using tissue samples from normal and failing human hearts. Atomistic simulations of myosin molecular dynamics suggest that these PTMs lead to meaningful alterations in structure, solvent exposure, and dynamics of certain regions of the protein. These data and simulations provide a foundation for further work to determine the precise functional significance of β-myosin heavy chain PTMs. The work will be of interest to cell biologists and cardiologists.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This report includes the identification and subsequent molecular dynamics analysis of posttranslational modifications of specific residues in beta-MHC in normal hearts and hearts in cardiac failure. The study is prompted by the possible regulatory roles of beta MHC in the generation of mechanical activity and possible reversion to fetal isoforms in cardiac failure. The identifications are followed by molecular dynamics simulations bearing on the stability of thick filament tail interactions and myosin head positioning.
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Reviewer #2 (Public Review):
1. The authors were aiming to determine what post-translational modifications were present on beta myosin motor protein and whether these were altered in two forms of heart failure. They then used molecular dynamics simulations to assess their potential effects on function and made some predictions based on the modeling.
2.. The strengths were that they found acetylations and phosphorylations albeit at very low frequency and they found that some of the PTMs were decreased in the failing heart.
3. A limitation is that only a relatively small number of samples was examined; with more samples, it might have been possible to make stronger conclusions. -
Reviewer #3 (Public Review):
The PTMs on β-myosin heavy chain reported in this study are likely to inspire further work into whether such modifications can produce discernable functional consequences on the sarcomere, cell, and heart scales. Molecular dynamics simulations provide useful context for selecting those PTMs which are most likely to merit further investigation. An interesting implication of these novel phosphorylation and acetylation sites is that they could interact with emerging small molecule therapies targeting myosin that may have been developed in the absence of realistic β-myosin PTMs.
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