ArticleProceedings of the National Academy of Sciences of the United States of America2020
Multivalent assembly of KRAS with the RAS-binding and cysteine-rich domains of CRAF on the membrane.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 80 citations in OpenAlex.
- Divergent CRD-Dependent Mechanisms Govern RAS Isoform-Selective Recruitment of CRAF and ARAF.bioRxiv : the preprint server for biology · 2026Article
- Article
- Allostery in Biomolecular Condensates.Journal of molecular biology · 2026Review
- Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding.Nature communications · 2026Article
- The BRAF-specific region suppresses cysteine-rich domain-lipid interaction independently of canonical autoinhibition by the 14-3-3 dimer.Protein science : a publication of the Protein Society · 2026Article
- DA-Raf synergistically binds to the plasma membrane and Ras to suppress ERK signaling.Life science alliance · 2025Article
- An in vitro BRAF activation assay elucidates molecular mechanisms driving disassembly of the autoinhibited BRAF state.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cryo-EM structures of CRAF/MEK1/14-3-3 complexes in autoinhibited and open-monomer states reveal features of RAF regulation.Nature communications · 2025Article
- RAS-membrane interaction and oligomerization: there is more than meets the eye.Biochemical Society transactions · 2025Review
- Article
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Motif-guided identification of KRAS-interacting proteins.BMC biology · 2024Article
- Effector Binding Sequentially Alters KRAS Dimerization on the Membrane: New Insights Into RAS-Mediated RAF Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.Nature communications · 2024Article
- Insight into molecular basis and dynamics of full-length CRaf kinase in cellular signaling mechanisms.Biophysical journal · 2024Article
- Regulation of RAF family kinases: new insights from recent structural and biochemical studies.Biochemical Society transactions · 2024Review
- RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations.Annual review of cancer biology · 2024Article
- SIRT4 as a novel interactor and candidate suppressor of C-RAF kinase in MAPK signaling.Life science alliance · 2024Article
- Reconstitution and characterization of BRAF in complex with 14-3-3 and KRAS4B on nanodiscs.Protein science : a publication of the Protein Society · 2024Article
- RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains.The Journal of cell biology · 2024Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
Membrane anchoring of farnesylated KRAS is critical for activation of RAF kinases, yet our understanding of how these proteins interact on the membrane is limited to isolated domains. The RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF engage KRAS and the plasma membrane, unleashing the kinase domain from autoinhibition. Due to experimental challenges, structural insight into this tripartite KRAS:RBD-CRD:membrane complex has relied on molecular dynamics simulations. Here, we report NMR studies of the KRAS:CRAF RBD-CRD complex. We found that the nucleotide-dependent KRAS-RBD interaction results in transient electrostatic interactions between KRAS and CRD, and we mapped the membrane interfaces of the CRD, RBD-CRD, and the KRAS:RBD-CRD complex. RBD-CRD exhibits dynamic interactions with the membrane through the canonical CRD lipid-binding site (CRD β7-8), as well as an alternative interface comprising β6 and the C terminus of CRD and β2 of RBD. Upon complex formation with KRAS, two distinct states were observed by NMR: State A was stabilized by membrane association of CRD β7-8 and KRAS α4-α5 while state B involved the C terminus of CRD, β3-5 of RBD, and part of KRAS α5. Notably, α4-α5, which has been proposed to mediate KRAS dimerization, is accessible only in state B. A cancer-associated mutation on the state B membrane interface of CRAF RBD (E125K) stabilized state B and enhanced kinase activity and cellular MAPK signaling. These studies revealed a dynamic picture of the assembly of the KRAS-CRAF complex via multivalent and dynamic interactions between KRAS, CRAF RBD-CRD, and the membrane.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.