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TitleStructural dynamics of RAF1-HSP90-CDC37 and HSP90 complexes reveal asymmetric client interactions and key structural elements.
Journal, issue, pagesCommun Biol, Vol. 7, Issue 1, Page 260, Year 2024
Publish dateMar 2, 2024
AuthorsLorenzo 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 Simanshu /
PubMed AbstractRAF 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 ...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.
External linksCommun Biol / PubMed:38431713 / PubMed Central
MethodsEM (single particle)
Resolution3.5 - 3.9 Å
Structure data

41816

8u1l

EMDB-41816, PDB-8u1l:
Cryo-EM structure of the RAF1-HSP90-CDC37 complex in the closed state
Method: EM (single particle) / Resolution: 3.7 Å

41817

8u1m

EMDB-41817, PDB-8u1m:
Cryo-EM structure of the HSP90 dimer (NTD-MD) in the semi-open state
Method: EM (single particle) / Resolution: 3.5 Å

41818

8u1n

EMDB-41818, PDB-8u1n:
Cryo-EM structure of the cross-linked HSP90 dimer (NTD-MD) in the semi-open state
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

Source
  • trichoplusia ni (cabbage looper)
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN/CHAPERONE / CRAF / RAF1 / HSP90 / CDC37 / SIGNALING PROTEIN-CHAPERONE complex / CHAPERONE / HSP / Crosslinked

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