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Resources » Paper

Vogel A et al. (2024) Nat Commun "UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome."

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  • Comments on Vogel A et al. (2024) Nat Commun "UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome." (0)

  • Overview

    PMID:
    39054317
    DOI:
    10.1038/s41467-024-50442-6
    Status:
    Publication type:
    Journal_article
    WormBase ID:
    WBPaper00067101

    Vogel A, Arnese R, Gudino Carrillo RM, Sehr D, Deszcz L, Bylicki A, Meinhart A, & Clausen T (2024). UNC-45 assisted myosin folding depends on a conserved FX3HY motif implicated in Freeman Sheldon Syndrome. Nat Commun, 15, 6272. doi:10.1038/s41467-024-50442-6

    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 FX<sub>3</sub>HY 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 FX<sub>3</sub>HY 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.

    Authors: Vogel A, Arnese R, Gudino Carrillo RM, Sehr D, Deszcz L, Bylicki A, Meinhart A, Clausen T


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