8BW9

Cryo-EM structure of the RAF activating complex KSR-MEK-CNK-HYP

8BW9 の概要

• エントリーDOI: 10.2210/pdb8bw9/pdb
• 関連するPDBエントリー: 8BW8
• EMDBエントリー: 16281
• 分子名称: Protein aveugle, Connector enhancer of KSR protein CNK, Dual specificity mitogen-activated protein kinase kinase dSOR1, ... (7 entities in total)
• 機能のキーワード: kinase suppressor of ras (ksr), dual specificity mitogen-activated protein kinase kinase (mek), connector enhancer of ksr (cnk), protein aveugle (ave), hyphen protein (hyp), protein complex, signaling protein
• 由来する生物種: Drosophila melanogaster (fruit fly); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 133225.40

構造登録者

Maisonneuve, P.,Fronzes, R.,Sicheri, F. (登録日: 2022-12-06, 公開日: 2024-02-21, 最終更新日: 2024-07-31)

主引用文献

Maisonneuve, P.,Sahmi, M.,Bergeron-Labrecque, F.,Ma, X.I.,Queguiner, J.,Arseneault, G.,Lefrancois, M.,Kurinov, I.,Fronzes, R.,Sicheri, F.,Therrien, M.
The CNK-HYP scaffolding complex promotes RAF activation by enhancing KSR-MEK interaction.
Nat.Struct.Mol.Biol., 31:1028-1038, 2024

PubMed Abstract: 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.

PubMed: 38388830
DOI: 10.1038/s41594-024-01233-6

実験手法

ELECTRON MICROSCOPY (3.32 Å)