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A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK
Damian F. Brennan1; Arvin C. Dar2; Nicholas T. Hertz2; WilliamC. H. Chao1; Alma L. Burlingame3; KevanM. Shokat2; David Barford1
2011
Source PublicationNature
ISSN1476-4687
Volume472Pages:366–369
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)1,2,3 functions as an essential scaffolding protein to coordinate the assembly of Raf–MEK–ERK complexes4,5. Here we integrate structural and biochemical studies to understand how KSR promotes stimulatory Raf phosphorylation of MEK (refs 67). 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 89), KSR2 self-associates through a side-to-side interface involving Arg 718, a residue identified in a genetic screen as a suppressor of Ras signalling1,2,3. 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.

DOIhttps://doi.org/10.1038/nature09860
Indexed BySCI
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000289724600043
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Cited Times [WOS]:154   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK
2.Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94107, USA
3.Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94107, USA
Recommended Citation
GB/T 7714
Damian F. Brennan,Arvin C. Dar,Nicholas T. Hertz,et al. A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK[J]. Nature,2011,472:366–369.
APA Damian F. Brennan.,Arvin C. Dar.,Nicholas T. Hertz.,WilliamC. H. Chao.,Alma L. Burlingame.,...&David Barford.(2011).A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.Nature,472,366–369.
MLA Damian F. Brennan,et al."A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK".Nature 472(2011):366–369.
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