Key result
The Y582S mutation in the conserved FX3HY motif of myosin, linked to Freeman Sheldon Syndrome, abrogates interaction with the UNC-45 chaperone and impairs myosin folding, leading to protein aggregation.
Why the study?
The molecular mechanism of UNC-45 as a hub in myosin quality control and folding was not fully understood.
The study reveals that the UNC-45 chaperone binds to a conserved FX3HY motif on myosin, and mutations in this motif, such as the Y582S mutation in Freeman Sheldon Syndrome, disrupt myosin folding and quality control.
No immediate clinical implications for Freeman-Sheldon syndrome; leaves open UNC-45 modulation as a research target.
Summary 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 3 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 3 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.
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Vogel et al. (2022) studied Freeman Sheldon Syndrome. Y582S mutation in the FX3HY motif vs. Wildtype myosin was evaluated on Myosin folding and interaction with UNC-45 chaperone. The Y582S mutation in the conserved FX3HY motif of myosin, linked to Freeman Sheldon Syndrome, abrogates interaction with the UNC-45 chaperone and impairs myosin folding, leading to protein aggregation.
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