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UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome

Author

Listed:
  • Antonia Vogel

    (Vienna BioCenter)

  • Renato Arnese

    (Vienna BioCenter)

  • Ricardo M. Gudino Carrillo

    (Vienna BioCenter
    Medical University)

  • Daria Sehr

    (Vienna BioCenter)

  • Luiza Deszcz

    (Vienna BioCenter)

  • Andrzej Bylicki

    (Vienna BioCenter)

  • Anton Meinhart

    (Vienna BioCenter)

  • Tim Clausen

    (Vienna BioCenter
    Vienna BioCenter Core Facilities)

Abstract

Myosin motors are critical for diverse motility functions, ranging from cytokinesis and endocytosis to muscle contraction. The UNC-45 chaperone controls myosin function mediating the folding, assembly, and degradation of the muscle protein. Here, we analyze the molecular mechanism of UNC-45 as a hub in myosin quality control. We show that UNC-45 forms discrete complexes with folded and unfolded myosin, forwarding them to downstream chaperones and E3 ligases. Structural analysis of a minimal chaperone:substrate complex reveals that UNC-45 binds to a conserved FX3HY motif in the myosin motor domain. Disrupting the observed interface by mutagenesis prevents myosin maturation leading to protein aggregation in vivo. We also show that a mutation in the FX3HY motif linked to the Freeman Sheldon Syndrome impairs UNC-45 assisted folding, reducing the level of functional myosin. These findings demonstrate that a faulty myosin quality control is a critical yet unexplored cause of human myopathies.

Suggested Citation

  • Antonia Vogel & Renato Arnese & Ricardo M. Gudino Carrillo & Daria Sehr & Luiza Deszcz & Andrzej Bylicki & Anton Meinhart & Tim Clausen, 2024. "UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50442-6
    DOI: 10.1038/s41467-024-50442-6
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