2026-08-10T08:11:44Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/267912025-12-18T12:57:23Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991
Repisalud
author
García-Alonso, Sara
author
Mesa, Pablo
author
Ovejero, Laura de la Puente
author
Aizpurua, Gonzalo
author
Lechuga, Carmen G
author
Zarzuela, Eduardo
author
Santiveri, Clara M
author
Sanclemente, Manuel
author
Muñoz, Javier
author
Musteanu, Mónica
author
Campos-Olivas, Ramón
author
Martínez-Torrecuadrada, Jorge
author
Barbacid, Mariano
author
Montoya, Guillermo
funder
European Research Council (ERC)
funder
Asociación Española contra el Cáncer
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
CRIS Cancer Foundation
funder
Comunidad de Madrid (Esapña)
funder
Novo Nordisk Foundation
2025-07-01T10:11:23Z
2025-07-01T10:11:23Z
2022-09-15
Mol Cell . 2022 Sep 15;82(18):3438-3452
Molecular Cell
36055235
https://hdl.handle.net/20.500.12105/26791
RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.
eng
MAPK signaling
RAF kinases
RAF1
cancer
cryo-EM
Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
research article
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structureoftheraf-2022.pdf