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Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis

Author

Listed:
  • Mónika Gönczi

    (University of Debrecen
    University of Debrecen)

  • João M. C. Teixeira

    (University of Padova)

  • Susana Barrera-Vilarmau

    (University of Padova)

  • Laura Mediani

    (University of Modena and Reggio Emilia G. Campi 287)

  • Francesco Antoniani

    (University of Modena and Reggio Emilia G. Campi 287)

  • Tamás Milán Nagy

    (University of Debrecen
    University of Debrecen Egyetem tér 1)

  • Krisztina Fehér

    (University of Debrecen
    University of Debrecen Egyetem tér 1)

  • Zsolt Ráduly

    (University of Debrecen
    University of Debrecen)

  • Viktor Ambrus

    (University of Debrecen)

  • József Tőzsér

    (University of Debrecen)

  • Endre Barta

    (University of Debrecen
    Hungarian University of Agriculture and Life Sciences)

  • Katalin E. Kövér

    (University of Debrecen
    University of Debrecen Egyetem tér 1)

  • László Csernoch

    (University of Debrecen
    University of Debrecen)

  • Serena Carra

    (University of Modena and Reggio Emilia G. Campi 287)

  • Monika Fuxreiter

    (University of Padova)

Abstract

During muscle cell differentiation, the alternatively spliced, acidic β-domain potentiates transcription of Myocyte-specific Enhancer Factor 2 (Mef2D). Sequence analysis by the FuzDrop method indicates that the β-domain can serve as an interaction element for Mef2D higher-order assembly. In accord, we observed Mef2D mobile nuclear condensates in C2C12 cells, similar to those formed through liquid-liquid phase separation. In addition, we found Mef2D solid-like aggregates in the cytosol, the presence of which correlated with higher transcriptional activity. In parallel, we observed a progress in the early phase of myotube development, and higher MyoD and desmin expression. In accord with our predictions, the formation of aggregates was promoted by rigid β-domain variants, as well as by a disordered β-domain variant, capable of switching between liquid-like and solid-like higher-order states. Along these lines, NMR and molecular dynamics simulations corroborated that the β-domain can sample both ordered and disordered interactions leading to compact and extended conformations. These results suggest that β-domain fine-tunes Mef2D higher-order assembly to the cellular context, which provides a platform for myogenic regulatory factors and the transcriptional apparatus during the developmental process.

Suggested Citation

  • Mónika Gönczi & João M. C. Teixeira & Susana Barrera-Vilarmau & Laura Mediani & Francesco Antoniani & Tamás Milán Nagy & Krisztina Fehér & Zsolt Ráduly & Viktor Ambrus & József Tőzsér & Endre Barta & , 2023. "Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37017-7
    DOI: 10.1038/s41467-023-37017-7
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    References listed on IDEAS

    as
    1. Elisa Cilia & Rita Pancsa & Peter Tompa & Tom Lenaerts & Wim F. Vranken, 2013. "From protein sequence to dynamics and disorder with DynaMine," Nature Communications, Nature, vol. 4(1), pages 1-10, December.
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    3. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
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