ArticleMolecular cell2022
RASopathy mutations provide functional insight into the BRAF cysteine-rich domain and reveal the importance of autoinhibition in BRAF regulation.
Article in Molecular cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 39 citations in OpenAlex.
- High-resolution measurement of ERK activation state reveals determinants of BRAF regulation and drug sensitivity.bioRxiv : the preprint server for biology · 2026Article
- KRAS G12C and KRAS G12D respond to lipid metabolism in an allele-specific manner.Journal of lipid research · 2026Article
- Kinetic Signatures of RAS-BRAF Engagement Reveal Isoform Selectivity, Oncogenic Amplification, and Mutation-Dependent Inhibitor Resistance.bioRxiv : the preprint server for biology · 2026Article
- Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding.Nature communications · 2026Article
- Molecular characterization of individuals with RASopathies: Spectrum of genetic variants in a large Indian cohort.Journal of genetics · 2026Article
- Case Report: Dual molecular diagnosis in complex congenital heart disease in an Ecuadorian patient with supravalvar aortic stenosis and pulmonary valve stenosis carrying pathogenic variants inFrontiers in pediatrics · 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
- Article
- A Narrative Review of RAS Mutations in Early-Stage Colorectal Cancer: Mechanisms and Clinical Implications.Medicina (Kaunas, Lithuania) · 2025Review
- Expression and role of deubiquitinating enzymes in thyroid carcinoma.Briefings in functional genomics · 2025Review
- Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort.Frontiers in immunology · 2025Observational
- Multiplexed profiling of intracellular protein abundance, activity, interactions and druggability with LABEL-seq.Nature methods · 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
- Multiplexed, multimodal profiling of the intracellular activity, interactions, and druggability of protein variants using LABEL-seq.bioRxiv : the preprint server for biology · 2024Article
- BRAF - a tumour-agnostic drug target with lineage-specific dependencies.Nature reviews. Clinical oncology · 2024Review
- Unveiling the domain-specific and RAS isoform-specific details of BRAF kinase regulation.eLife · 2023Article
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9 authors at 3 institutions in 1 country.
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Abstract
BRAF is frequently mutated in human cancer and the RASopathy syndromes, with RASopathy mutations often observed in the cysteine-rich domain (CRD). Although the CRD participates in phosphatidylserine (PS) binding, the RAS-RAF interaction, and RAF autoinhibition, the impact of these activities on RAF function in normal and disease states is not well characterized. Here, we analyze a panel of CRD mutations and show that they increase BRAF activity by relieving autoinhibition and/or enhancing PS binding, with relief of autoinhibition being the major factor determining mutation severity. Further, we show that CRD-mediated autoinhibition prevents the constitutive plasma membrane localization of BRAF that causes increased RAS-dependent and RAS-independent function. Comparison of the BRAF- and CRAF-CRDs also indicates that the BRAF-CRD is a stronger mediator of autoinhibition and PS binding, and given the increased catalytic activity of BRAF, our studies reveal a more critical role for CRD-mediated autoinhibition in BRAF regulation.
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