![]() Chaperones perform this protective function by facilitating proper protein folding and assembly, refolding misfolded proteins to prevent their aggregation, and delivering damaged proteins for disposal 7, 8, 9, 10. Molecular chaperones are a diverse group of proteins that play a crucial role in protecting cells from the dangers of protein misfolding and aggregation-phenomena that have been implicated in a host of debilitating human conditions, such as Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as many neuromuscular disorders and myopathies 1, 2, 3, 4, 5, 6. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1. ![]() These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. ![]() Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins.
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