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TitleThe CNK-HYP scaffolding complex promotes RAF activation by enhancing KSR-MEK interaction.
Journal, issue, pagesNat Struct Mol Biol, Year 2024
Publish dateFeb 22, 2024
AuthorsPierre Maisonneuve / Malha Sahmi / Fanny Bergeron-Labrecque / Xianjie Iris Ma / Juliette Queguiner / Geneviève Arseneault / Martin Lefrançois / Igor Kurinov / Rémi Fronzes / Frank Sicheri / Marc Therrien /
PubMed AbstractThe RAS-MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and ...The RAS-MAPK pathway regulates cell proliferation, differentiation and survival, and its dysregulation is associated with cancer development. The pathway minimally comprises the small GTPase RAS and the kinases RAF, MEK and ERK. Activation of RAF by RAS is notoriously intricate and remains only partially understood. There are three RAF isoforms in mammals (ARAF, BRAF and CRAF) and two related pseudokinases (KSR1 and KSR2). RAS-mediated activation of RAF depends on an allosteric mechanism driven by the dimerization of its kinase domain. Recent work on human RAFs showed that MEK binding to KSR1 promotes KSR1-BRAF heterodimerization, which leads to the phosphorylation of free MEK molecules by BRAF. Similar findings were made with the single Drosophila RAF homolog. Here we show that the fly scaffold proteins CNK and HYP stabilize the KSR-MEK interaction, which in turn enhances RAF-KSR heterodimerization and RAF activation. The cryogenic electron microscopy structure of the minimal KSR-MEK-CNK-HYP complex reveals a ring-like arrangement of the CNK-HYP complex allowing CNK to simultaneously engage KSR and MEK, thus stabilizing the binary interaction. Together, these results illuminate how CNK contributes to RAF activation by stimulating the allosteric function of KSR and highlight the diversity of mechanisms impacting RAF dimerization as well as the regulatory potential of the KSR-MEK interaction.
External linksNat Struct Mol Biol / PubMed:38388830
MethodsEM (single particle) / X-ray diffraction
Resolution2.1 - 3.32 Å
Structure data

EMDB-16281, PDB-8bw9:
Cryo-EM structure of the RAF activating complex KSR-MEK-CNK-HYP
Method: EM (single particle) / Resolution: 3.32 Å

PDB-8bw8:
Crystal structure of the dCNK-SAM-CRIC-PDZ/dHYP-SAM complex
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

Chemicals

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-HOH:
WATER / Water

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-QOM:
Trametinib / medication, anticancer, inhibitor*YM / Trametinib

ChemComp-MG:
Unknown entry

Source
  • drosophila melanogaster (fruit fly)
KeywordsSIGNALING PROTEIN / Scaffolding protein / Connector enhancer of KSR (CNK) / Protein Aveugle (AVE) / Hyphen protein (HYP) / COmplex protein / Sterile alpha motif (SAM) domain / conserved region in CNK (CRIC) domain / PSD-95 / Dlg / and Zo-1. (PDZ) domain. / Kinase suppressor of Ras (KSR) / Dual specificity mitogen-activated protein kinase kinase (MEK) / protein complex

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