Linked Life Data

21441910

Source:http://linkedlifedata.com/resource/pubmed/id/21441910

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7343
pubmed:dateCreated
2011-4-22
pubmed:databankReference
pubmed:abstractText
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 ?G 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:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1476-4687
pubmed:author
pubmed:issnType
Electronic
pubmed:day
21
pubmed:volume
472
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
366-9
pubmed:meshHeading
pubmed-meshheading:21441910-Adenosine Triphosphate, pubmed-meshheading:21441910-Allosteric Regulation, pubmed-meshheading:21441910-Animals, pubmed-meshheading:21441910-Biocatalysis, pubmed-meshheading:21441910-Catalytic Domain, pubmed-meshheading:21441910-Crystallography, X-Ray, pubmed-meshheading:21441910-Enzyme Activation, pubmed-meshheading:21441910-Extracellular Signal-Regulated MAP Kinases, pubmed-meshheading:21441910-Humans, pubmed-meshheading:21441910-MAP Kinase Kinase 1, pubmed-meshheading:21441910-Models, Molecular, pubmed-meshheading:21441910-Phosphorylation, pubmed-meshheading:21441910-Protein Multimerization, pubmed-meshheading:21441910-Protein Structure, Quaternary, pubmed-meshheading:21441910-Protein-Serine-Threonine Kinases, pubmed-meshheading:21441910-Proto-Oncogene Proteins B-raf, pubmed-meshheading:21441910-Rabbits, pubmed-meshheading:21441910-Signal Transduction
pubmed:year
2011
pubmed:articleTitle
A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.
pubmed:affiliation
Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural