Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation

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Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. / García-Alonso, Sara; Mesa, Pablo; Ovejero, Laura de la Puente; Aizpurua, Gonzalo; Lechuga, Carmen G; Zarzuela, Eduardo; Santiveri, Clara M; Sanclemente, Manuel; Muñoz, Javier; Musteanu, Mónica; Campos-Olivas, Ramón; Martínez-Torrecuadrada, Jorge; Barbacid, Mariano; Montoya, Guillermo.

In: Molecular Cell, Vol. 82, No. 18, 2022, p. 3438-3452.e8.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

García-Alonso, S, Mesa, P, Ovejero, LDLP, Aizpurua, G, Lechuga, CG, Zarzuela, E, Santiveri, CM, Sanclemente, M, Muñoz, J, Musteanu, M, Campos-Olivas, R, Martínez-Torrecuadrada, J, Barbacid, M & Montoya, G 2022, 'Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation', Molecular Cell, vol. 82, no. 18, pp. 3438-3452.e8. https://doi.org/10.1016/j.molcel.2022.08.012

APA

García-Alonso, S., Mesa, P., Ovejero, L. D. L. P., Aizpurua, G., Lechuga, C. G., Zarzuela, E., Santiveri, C. M., Sanclemente, M., Muñoz, J., Musteanu, M., Campos-Olivas, R., Martínez-Torrecuadrada, J., Barbacid, M., & Montoya, G. (2022). Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Molecular Cell, 82(18), 3438-3452.e8. https://doi.org/10.1016/j.molcel.2022.08.012

Vancouver

García-Alonso S, Mesa P, Ovejero LDLP, Aizpurua G, Lechuga CG, Zarzuela E et al. Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Molecular Cell. 2022;82(18):3438-3452.e8. https://doi.org/10.1016/j.molcel.2022.08.012

Author

García-Alonso, Sara ; Mesa, Pablo ; Ovejero, Laura de la Puente ; Aizpurua, Gonzalo ; Lechuga, Carmen G ; Zarzuela, Eduardo ; Santiveri, Clara M ; Sanclemente, Manuel ; Muñoz, Javier ; Musteanu, Mónica ; Campos-Olivas, Ramón ; Martínez-Torrecuadrada, Jorge ; Barbacid, Mariano ; Montoya, Guillermo. / Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. In: Molecular Cell. 2022 ; Vol. 82, No. 18. pp. 3438-3452.e8.

Bibtex

@article{43cce53cc58d458885a18d694c794c4c,
title = "Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation",
abstract = "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.",
author = "Sara Garc{\'i}a-Alonso and Pablo Mesa and Ovejero, {Laura de la Puente} and Gonzalo Aizpurua and Lechuga, {Carmen G} and Eduardo Zarzuela and Santiveri, {Clara M} and Manuel Sanclemente and Javier Mu{\~n}oz and M{\'o}nica Musteanu and Ram{\'o}n Campos-Olivas and Jorge Mart{\'i}nez-Torrecuadrada and Mariano Barbacid and Guillermo Montoya",
note = "Copyright {\textcopyright} 2022 Elsevier Inc. All rights reserved.",
year = "2022",
doi = "10.1016/j.molcel.2022.08.012",
language = "English",
volume = "82",
pages = "3438--3452.e8",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "18",

}

RIS

TY - JOUR

T1 - Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation

AU - García-Alonso, Sara

AU - Mesa, Pablo

AU - Ovejero, Laura de la Puente

AU - Aizpurua, Gonzalo

AU - Lechuga, Carmen G

AU - Zarzuela, Eduardo

AU - Santiveri, Clara M

AU - Sanclemente, Manuel

AU - Muñoz, Javier

AU - Musteanu, Mónica

AU - Campos-Olivas, Ramón

AU - Martínez-Torrecuadrada, Jorge

AU - Barbacid, Mariano

AU - Montoya, Guillermo

N1 - Copyright © 2022 Elsevier Inc. All rights reserved.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2022.08.012

DO - 10.1016/j.molcel.2022.08.012

M3 - Journal article

C2 - 36055235

VL - 82

SP - 3438-3452.e8

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 18

ER -

ID: 318700456