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

Antonia Vogel, Renato Arnese, Ricardo M. Gudino Carrillo, Daria Sehr, Luiza Deszcz, Andrzej Bylicki, Anton Meinhart and Tim Clausen ()
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Antonia Vogel: Vienna BioCenter
Renato Arnese: Vienna BioCenter
Ricardo M. Gudino Carrillo: Vienna BioCenter
Daria Sehr: Vienna BioCenter
Luiza Deszcz: Vienna BioCenter
Andrzej Bylicki: Vienna BioCenter
Anton Meinhart: Vienna BioCenter
Tim Clausen: Vienna BioCenter

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50442-6

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