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bioRxiv · 10.1101/2021.11.21.469462

Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and non-ischemic human hearts

Parvatiyar, M. S.·Landim-Vieira, M.·Childers, M. C.·Wacker, A. L.·Garcia, M. R.·He, H.·Singh, R.·Brundage, E. A.·Johnston, J. R.·Whitson, B. A.·Chase, P. B.·Janssen, P. M.·Regnier, M.·Biesiadecki, B. J.·Pinto, J. R.
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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 beta-myosin heavy chain ({beta}-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 1s structure and dynamics - known to regulate ADP-release, ATPase activity, and sliding velocity. Our study suggests that {beta}-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 {beta}-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.

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Parvatiyar, M. S., Landim-Vieira, M., Childers, M. C., Wacker, A. L., Garcia, M. R., He, H., Singh, R., Brundage, E. A., Johnston, J. R., Whitson, B. A., Chase, P. B., Janssen, P. M., Regnier, M., Biesiadecki, B. J., Pinto, J. R.. 2021-11-22. Post-translational modification patterns on β-myosin heavy chain are altered in ischemic and non-ischemic human hearts. https://doi.org/10.1101/2021.11.21.469462

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