8U1L

Cryo-EM structure of the RAF1-HSP90-CDC37 complex in the closed state

Summary for 8U1L

• Entry DOI: 10.2210/pdb8u1l/pdb
• EMDB information: 41816 41817 41818
• Descriptor: Heat shock protein 83, RAF proto-oncogene serine/threonine-protein kinase, Hsp90 co-chaperone Cdc37, N-terminally processed, ... (5 entities in total)
• Functional Keywords: craf, raf1, hsp90, cdc37, signaling protein-chaperone complex, signaling protein/chaperone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 286351.05

Authors

Finci, L.I.,Simanshu, D.K. (deposition date: 2023-09-01, release date: 2024-03-13, Last modification date: 2024-10-23)

Primary citation

Finci, L.I.,Chakrabarti, M.,Gulten, G.,Finney, J.,Grose, C.,Fox, T.,Yang, R.,Nissley, D.V.,McCormick, F.,Esposito, D.,Balius, T.E.,Simanshu, D.K.
Structural dynamics of RAF1-HSP90-CDC37 and HSP90 complexes reveal asymmetric client interactions and key structural elements.
Commun Biol, 7:260-260, 2024

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

PubMed: 38431713
DOI: 10.1038/s42003-024-05959-3

Experimental method

ELECTRON MICROSCOPY (3.7 Å)