ArticleNature communications2025
Cryo-EM structures of CRAF/MEK1/14-3-3 complexes in autoinhibited and open-monomer states reveal features of RAF regulation.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Monovalent Nondegrading Molecular Glues: An Updated Overview of Emerging Mechanisms and Therapeutic Development.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Extracellular Vesicles Derived from Resveratrol-Treated BMSCs Promote the Repair of Bone Defects in Osteoporotic Rats.Stem cell reviews and reports · 2026Article
- Structural and Biophysical Analyses of Human MEK2 in Complex with Two Inhibitors Reveal the Determinants of Isoform-Dependent Inhibitor Binding.International journal of molecular sciences · 2026Article
- Cryo-EM structure and biochemical characterization of a BRAF/CRAF heterodimer: Negative charge in the NtA motif is not required for RAF activation.bioRxiv : the preprint server for biology · 2026Article
- MEK interactions tune RAF kinase sensitivity to conformation-selective inhibition.Nature chemical biology · 2026Article
- Restoring the 14-3-3/CRAF regulatory interaction in Noonan syndrome using molecular glues.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Preservation of Human Colonic Stem Cells Requires an ERK Dynamics Checkpoint Mediated by AKT.bioRxiv : the preprint server for biology · 2026Article
- A computational rule-based model of MAPK/ERK system regulation.Scientific reports · 2026Article
- Modulation of the 14-3-3σ/C-RAF "Auto"inhibited Complex by Molecular Glues.Journal of the American Chemical Society · 2026Article
- Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding.Nature communications · 2026Article
- Molecular basis of mitogen-activated protein kinase ERK2 activation by its upstream kinase MEK1.bioRxiv : the preprint server for biology · 2026Article
- Review
- In-cell single-molecule FRET measurement of cytosolic RAF proteins to investigate the structural states and kinetics among them.Frontiers in molecular biosciences · 2025Article
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Authors and funding
10 authors.
Funding
Abstract
CRAF (RAF1) is one of three RAF-family kinases that initiate MAP kinase signaling in response to activated RAS and is essential for oncogenic signaling from mutant KRAS. Like BRAF, CRAF is regulated by 14-3-3 engagement and by intramolecular autoinhibitory interactions of its N-terminal regulatory region. Unlike BRAF, it is thought to require tyrosine phosphorylation in its N-terminal acidic (NtA) motif for full catalytic activation. Here we describe cryo-EM reconstructions of full-length CRAF in complex with MEK1 and a 14-3-3 dimer. These structures reveal a fully autoinhibited conformation analogous to that observed for BRAF and two "open monomer" states in which the inhibitory interactions of the CRD and 14-3-3 dimer are released or rearranged, but the kinase domain remains inactive. Structure-function studies of the NtA motif indicate that phosphorylation or acidic mutations in this segment increase catalytic activity by destabilizing the inactive conformation of the kinase domain. Collectively, these studies provide a structural foundation for understanding the shared and unique regulatory features of CRAF and will inform efforts to selectively block CRAF signaling in cancer.
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