Tertiary structure and conformational dynamics of the anti-amyloidogenic chaperone DNAJB6b at atomistic resolution

• Published in: Nature communications Vol. 15; no. 1; p. 3285
• Main Authors: Adupa, Vasista, Ustyantseva, Elizaveta, Kampinga, Harm H, Onck, Patrick R
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.04.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Aggregation; Amyloidogenesis; Binding; Dystrophy; F 1 region; Heat shock; Heat shock proteins; Heat-Shock Proteins - metabolism; Helices; Homology; HSP40 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins - metabolism; Hsp70 protein; Humans; Molecular Chaperones - metabolism; Molecular Conformation; Molecular dynamics; Molecular Dynamics Simulation; Muscular Dystrophies, Limb-Girdle; Muscular dystrophy; Mutation; Probability theory; Protein structure; Proteins; Quality control; Simulation; Substrates; Tertiary structure; Toxicity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46587-z

DNAJB6b is a molecular chaperone of the heat shock protein network, shown to play a crucial role in preventing aggregation of several disease-related intrinsically disordered proteins. Using homology modeling and microsecond-long all-atom molecular dynamics (MD) simulations, we show that monomeric DNAJB6b is a transiently interconverting protein cycling between three states: a closed state, an open state (both abundant), and a less abundant extended state. Interestingly, the reported regulatory autoinhibitory anchor between helix V in the G/F region and helices II/III of the J-domain, which obstructs the access of Hsp70 to the J-domain remains present in all three states. This possibly suggests a mechanistically intriguing regulation in which DNAJB6b only becomes exposed when loaded with substrates that require Hsp70 processing. Our MD results of DNAJB6b carrying mutations in the G/F region that are linked to limb-girdle muscular dystrophy type D1 (LGMDD1) show that this G/F region becomes highly dynamic, pointing towards a spontaneous release of the autoinhibitory helix V from helices II/III. This would increase the probability of non-functional Hsp70 interactions to DNAJB6b without substrates. Our cellular data indeed confirm that non-substrate loaded LGMDD1 mutants have aberrant interactions with Hsp70.