ArticleCellular and molecular life sciences : CMLS2022
The mechanism of activation of MEK1 by B-Raf and KSR1.
Article in Cellular and molecular life sciences : CMLS, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 35 citations in OpenAlex.
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- Allostery in Biomolecular Condensates.Journal of molecular biology · 2026Review
- ucOCN Promotes Testosterone Synthesis via the PKA-MAPK/ERK-CREB Signaling Pathway in Porcine Leydig Cells.Cells · 2025Article
- Kinase suppressor of Ras 1 (KSR1) promotes liver carcinogenesis via activation of the RAS/RAF/MEK/ERK signaling pathway.JHEP reports : innovation in hepatology · 2025Article
- ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events.Journal of molecular biology · 2025Article
- Kinase signaling cascades: an updated mechanistic landscape.Chemical science · 2025Review
- Targeted therapy of papillary craniopharyngioma.Medical oncology (Northwood, London, England) · 2025Review
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Drug resistance and tumor heterogeneity: cells and ensembles.Biophysical reviews · 2025Review
- Genome-wide association study and subsequent functional analysis reveal regulatory mechanism underlying piglet diarrhea.Animal bioscience · 2025Article
- ZC3H13 promotes autophagy in bladder cancer through m6A methylation modification of PJA2 and ubiquitination of KSR1.Human cell · 2024Article
- Imaging the Raf-MEK-ERK Signaling Cascade in Living Cells.International journal of molecular sciences · 2024Article
- Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification.International journal of molecular sciences · 2024Article
- Impact of Phosphorylation at Various Sites on the Active Pocket of Human Ferrochelatase: Insights from Molecular Dynamics Simulations.International journal of molecular sciences · 2024Article
- Cancer and Autism: How PTEN Mutations Degrade Function at the Membrane and Isoform Expression in the Human Brain.Journal of molecular biology · 2023Article
- Protein conformational ensembles in function: roles and mechanisms.RSC chemical biology · 2023Review
- Analysis of RAS and drug induced homo- and heterodimerization of RAF and KSR1 proteins in living cells using split Nanoluc luciferase.Cell communication and signaling : CCS · 2023Article
- Strategy toward Kinase-Selective Drug Discovery.Journal of chemical theory and computation · 2023Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
MEK1 interactions with B-Raf and KSR1 are key steps in Ras/Raf/MEK/ERK signaling. Despite this, vital mechanistic details of how these execute signal transduction are still enigmatic. Among these is why, despite B-Raf and KSR1 kinase domains similarity, the B-Raf/MEK1 and KSR1/MEK1 complexes have distinct contributions to MEK1 activation, and broadly, what is KSR1's role. Our molecular dynamics simulations clarify these still unresolved ambiguities. Our results reveal that the proline-rich (P-rich) loop of MEK1 plays a decisive role in MEK1 activation loop (A-loop) phosphorylation. In the inactive B-Raf/MEK1 heterodimer, the collapsed A-loop of B-Raf interacts with the P-rich loop and A-loop of MEK1, minimizing MEK1 A-loop fluctuation and preventing it from phosphorylation. In the active B-Raf/MEK1 heterodimer, the P-rich loop moves in concert with the A-loop of B-Raf as it extends. This reduces the number of residues interacting with MEK1 A-loop, allowing increased A-loop fluctuation, and bringing Ser222 closer to ATP for phosphorylation. B-Raf αG-helix Arg662 promotes MEK1 activation by orienting Ser218 towards ATP. In KSR1/MEK1, the KSR1 αG-helix has Ala826 in place of B-Raf Arg662. This difference results in much fewer interactions between KSR1 αG-helix and MEK1 A-loop, thus a more flexible A-loop. We postulate that if KSR1 were to adopt an active configuration with an extended A-loop as seen in other protein kinases, then the MEK1 P-rich loop would extend in a similar manner, as seen in the active B-Raf/MEK1 heterodimer. This would result in highly flexible MEK1 A-loop, and KSR1 functioning as an active, B-Raf-like, kinase.
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