2Y4I

KSR2-MEK1 heterodimer

2Y4I の概要

• エントリーDOI: 10.2210/pdb2y4i/pdb
• 分子名称: KINASE SUPPRESSOR OF RAS 2, DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1, ADENOSINE-5'-TRIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: transferase, ksr1
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81545.19

構造登録者

Brennan, D.F.,Barford, D. (登録日: 2011-01-06, 公開日: 2011-01-19, 最終更新日: 2023-12-20)

主引用文献

Brennan, D.F.,Dar, A.C.,Hertz, N.T.,Chao, W.,Burlingame, A.L.,Shokat, K.M.,Barford, D.
A Raf-Induced Allosteric Transition of Ksr Stimulates Ksr and Raf Phosphorylation of Mek
Nature, 472:366-, 2011

PubMed Abstract: In metazoans, the Ras-Raf-MEK (mitogen-activated protein-kinase kinase)-ERK (extracellular signal-regulated kinase) signalling pathway relays extracellular stimuli to elicit changes in cellular function and gene expression. Aberrant activation of this pathway through oncogenic mutations is responsible for a large proportion of human cancer. Kinase suppressor of Ras (KSR) functions as an essential scaffolding protein to coordinate the assembly of Raf-MEK-ERK complexes. Here we integrate structural and biochemical studies to understand how KSR promotes stimulatory Raf phosphorylation of MEK (refs 6, 7). We show, from the crystal structure of the kinase domain of human KSR2 (KSR2(KD)) in complex with rabbit MEK1, that interactions between KSR2(KD) and MEK1 are mediated by their respective activation segments and C-lobe αG helices. Analogous to BRAF (refs 8, 9), KSR2 self-associates through a side-to-side interface involving Arg 718, a residue identified in a genetic screen as a suppressor of Ras signalling. ATP is bound to the KSR2(KD) catalytic site, and we demonstrate KSR2 kinase activity towards MEK1 by in vitro assays and chemical genetics. In the KSR2(KD)-MEK1 complex, the activation segments of both kinases are mutually constrained, and KSR2 adopts an inactive conformation. BRAF allosterically stimulates the kinase activity of KSR2, which is dependent on formation of a side-to-side KSR2-BRAF heterodimer. Furthermore, KSR2-BRAF heterodimerization results in an increase of BRAF-induced MEK phosphorylation via the KSR2-mediated relay of a signal from BRAF to release the activation segment of MEK for phosphorylation. We propose that KSR interacts with a regulatory Raf molecule in cis to induce a conformational switch of MEK, facilitating MEK's phosphorylation by a separate catalytic Raf molecule in trans.

PubMed: 21441910
DOI: 10.1038/NATURE09860

実験手法

X-RAY DIFFRACTION (3.46 Å)