Structural dynamics of RAF1-HSP90-CDC37 and HSP90 complexes reveal asymmetric client interactions and key structural elements

• DOI: 10.1038/s42003-024-05959-3
• Publication Date: 2024-03-02T15:03:17Z
• Authors: Lorenzo I. Finci; Mayukh Chakrabarti; Gulcin Gulten; Joseph Finney; Carissa Grose; Tara Fox; Renbin Yang; Dwight V. Nissley; Frank McCormick; Dominic Esposito; Trent E. Balius; Dhirendra K. Sima...
• Keywords: 570; Chaperonins; QH301-705.5; Humans; Cell Cycle Proteins; HSP90 Heat-Shock Proteins; Biology (General); 540; Article; Protein Binding; Molecular Chaperones

RAF kinases are integral to the RAS-MAPK signaling pathway, and proper RAF1 folding relies on its interaction with chaperone HSP90 cochaperone CDC37. Understanding intricate molecular interactions governing is crucial for comprehending this process. Here, we present a cryo-EM structure of closed-state RAF1-HSP90-CDC37 complex, where C-lobe kinase domain binds one side dimer, an unfolded N-lobe segment threads through center dimer. CDC37 C-lobe, mimicking HxNI motif. We also describe structures dimers without CDC37, displaying only N-terminal middle domains, which term semi-open state. Employing 1 μs atomistic simulations, energetic decomposition, comparative structural analysis, elucidate dynamics within these complexes. Our quantitative analysis reveals that bridges HSP90-RAF1 interaction, asymmetrically, elements engage RAF1's region. Additionally, N- C-terminal stabilize dimers, in rearrange between closed states. findings provide valuable insight into contributions mediating client folding.