Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
Medical University, Vienna, Austria.
Nat Commun. 2024 Jul 25;15(1):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 FXHY 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 FXHY 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.
肌球蛋白马达对于各种运动功能至关重要，包括胞质分裂和内吞作用以及肌肉收缩。UNC-45 伴侣蛋白控制肌球蛋白的功能，调节肌肉蛋白的折叠、组装和降解。在这里，我们分析了 UNC-45 作为肌球蛋白质量控制中心的分子机制。我们表明，UNC-45 与折叠和未折叠的肌球蛋白形成离散的复合物，将它们转交给下游伴侣蛋白和 E3 连接酶。对最小伴侣蛋白：底物复合物的结构分析表明，UNC-45 结合在肌球蛋白马达结构域中的保守 FXHY 基序上。通过突变破坏观察到的界面会阻止肌球蛋白成熟，导致体内蛋白质聚集。我们还表明，与弗里曼-谢尔登综合征相关的 FXHY 基序突变会损害 UNC-45 辅助折叠，降低功能性肌球蛋白的水平。这些发现表明，肌球蛋白质量控制的缺陷是人类肌病的一个关键但尚未探索的原因。
