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
Further reading
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- Structural Biology and Molecular Biophysics
In eukaryotes, RNAs transcribed by RNA Pol II are modified at the 5′ end with a 7-methylguanosine (m7G) cap, which is recognized by the nuclear cap binding complex (CBC). The CBC plays multiple important roles in mRNA metabolism, including transcription, splicing, polyadenylation, and export. It promotes mRNA export through direct interaction with a key mRNA export factor, ALYREF, which in turn links the TRanscription and EXport (TREX) complex to the 5′ end of mRNA. However, the molecular mechanism for CBC-mediated recruitment of the mRNA export machinery is not well understood. Here, we present the first structure of the CBC in complex with an mRNA export factor, ALYREF. The cryo-EM structure of CBC-ALYREF reveals that the RRM domain of ALYREF makes direct contact with both the NCBP1 and NCBP2 subunits of the CBC. Comparing CBC-ALYREF with other cellular complexes containing CBC and/or ALYREF components provides insights into the coordinated events during mRNA transcription, splicing, and export.
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- Structural Biology and Molecular Biophysics
Under physiological conditions, proteins continuously undergo structural fluctuations on different timescales. Some conformations are only sparsely populated, but still play a key role in protein function. Thus, meaningful structure–function frameworks must include structural ensembles rather than only the most populated protein conformations. To detail protein plasticity, modern structural biology combines complementary experimental and computational approaches. In this review, we survey available computational approaches that integrate sparse experimental data from electron paramagnetic resonance spectroscopy with molecular modeling techniques to derive all-atom structural models of rare protein conformations. We also propose strategies to increase the reliability and improve efficiency using deep learning approaches, thus advancing the field of integrative structural biology.
