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SUMO interacting motif (SIM) of S100A1 is critical for S100A1 post-translational protein stability

View ORCID ProfileZegeye H. Jebessa, Manuel Glaser, Jemmy Zhao, Andrea Schneider, Ramkumar Seenivasan, Martin Busch, Julia Ritterhoff, Rebecca C. Wade, Patrick Most
doi: https://doi.org/10.1101/2023.01.18.524665
Zegeye H. Jebessa
1Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
2German Center for Heart Research (DZHK), Partner Site Heidelberg-Mannheim, Germany
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  • ORCID record for Zegeye H. Jebessa
Manuel Glaser
3Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
6Informatics for Life, Heidelberg, Germany
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Jemmy Zhao
1Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
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Andrea Schneider
1Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
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Ramkumar Seenivasan
4Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany
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Martin Busch
1Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
2German Center for Heart Research (DZHK), Partner Site Heidelberg-Mannheim, Germany
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Julia Ritterhoff
1Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
2German Center for Heart Research (DZHK), Partner Site Heidelberg-Mannheim, Germany
6Informatics for Life, Heidelberg, Germany
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Rebecca C. Wade
3Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany
4Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, Heidelberg, Germany
5Interdisciplinary Center for Scientific Computing (IWR), Heidelberg, Germany
6Informatics for Life, Heidelberg, Germany
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Patrick Most
1Molecular and Translational Cardiology, Department of Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany
2German Center for Heart Research (DZHK), Partner Site Heidelberg-Mannheim, Germany
6Informatics for Life, Heidelberg, Germany
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  • For correspondence: patrick.most@med.uni-heidelberg.de
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Abstract

S100A1 is a small EF-type Ca2+ sensor protein that belongs to the multigenic S100 protein family. It is abundantly expressed in cardiomyocytes (CMs) and has been described as a key regulator of CM performance due to its unique ability to interact with structural contractile proteins, regulators of cardiac Ca2+ cycling, and mitochondrial proteins. However, our understanding of the molecular mechanisms regulating S100A1 protein levels is limited. We used the bioinformatics tool GPS-SUMO2.0 to identify a putative SUMO interacting motif (SIM) on S100A1. Consistently, a S100A1:SUMO interaction assay showed a Ca2+-dependent interaction of S100A1 with SUMO proteins. In neonatal rat ventricular myocytes (NRVM) and COS1 cells, S100A1 protein abundance increased in the presence of overexpressed SUMO1 without affecting the S100A1 mRNA transcript. We then generated S100A1 truncation mutants, where the SIM motif was removed by truncation or in which the core residues of the SIM motif (residues 77-79) were deleted or replaced by alanine. In COS1 cells and NRVM, overexpression of these S100A1 mutants led to elevated S100A1 mutant mRNA levels but failed to produce respective protein levels. Protein expression of these mutants could be rescued from degradation by addition of the proteasome inhibitor MG-132. By using an information-driven approach to dock the three-dimensional structures of S100A1 and SUMO, we predict a novel interaction mode between the SIM in S100A1 and SUMO. This study shows an important role of SUMO:SIM-mediated protein:protein interaction in the regulation of post-translational protein stability, and provides mechanistic insights into the indispensability of the core SIM for S100A1 post-translational stability.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations (Non-standard abbreviations and acronyms)

    SUMO
    Small Ubiquitin-like Modifier
    SIM SUMO
    interacting motif
    Ub
    Ubiquitin
    NRVM
    Neonatal rat ventricular myocyte
    ARVM
    Adult rat ventricular myocyte
    EGFP
    Enhanced green fluorescence protein
    DSIM
    S100A1-SIM deleted mutant
    CMV
    cytomegalovirus
    MOI
    Multiplicity of infection
    CM
    cardiomyocyte
    HFrEF
    heart failure with reduced ejection fraction
    PTM
    post-translational modifications
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    Posted January 19, 2023.
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    SUMO interacting motif (SIM) of S100A1 is critical for S100A1 post-translational protein stability
    Zegeye H. Jebessa, Manuel Glaser, Jemmy Zhao, Andrea Schneider, Ramkumar Seenivasan, Martin Busch, Julia Ritterhoff, Rebecca C. Wade, Patrick Most
    bioRxiv 2023.01.18.524665; doi: https://doi.org/10.1101/2023.01.18.524665
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    SUMO interacting motif (SIM) of S100A1 is critical for S100A1 post-translational protein stability
    Zegeye H. Jebessa, Manuel Glaser, Jemmy Zhao, Andrea Schneider, Ramkumar Seenivasan, Martin Busch, Julia Ritterhoff, Rebecca C. Wade, Patrick Most
    bioRxiv 2023.01.18.524665; doi: https://doi.org/10.1101/2023.01.18.524665

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