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TitleCryo-EM structures of CRAF/MEK1/14-3-3 complexes in autoinhibited and open-monomer states reveal features of RAF regulation.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 8150, Year 2025
Publish dateSep 1, 2025
AuthorsDong Man Jang / Kayla Boxer / Byung Hak Ha / Emre Tkacik / Talya Levitz / Shaun Rawson / Rebecca J Metivier / Anna Schmoker / Hyesung Jeon / Michael J Eck /
PubMed AbstractCRAF (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 ...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.
External linksNat Commun / PubMed:40890113 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.9 Å
Structure data

48397

9mmp

EMDB-48397, PDB-9mmp:
Cryo-EM structure of CRAF/MEK1/14-3-3 complex (autoinhibited conformation)
Method: EM (single particle) / Resolution: 3.4 Å

48399

9mmq

EMDB-48399, PDB-9mmq:
Cryo-EM structure of CRAF/MEK1 complex (kinase domain)
Method: EM (single particle) / Resolution: 2.9 Å

48401

9mmr

EMDB-48401, PDB-9mmr:
Cryo-EM structure of CRAF/MEK1/14-3-3 complex (open monomer conformation, CRAF Y340D/Y341D mutant)
Method: EM (single particle) / Resolution: 3.9 Å

48402

9mms

EMDB-48402, PDB-9mms:
Cryo-EM structure of CRAF/MEK1 complex (kinase domain, CRAF Y340D/Y341D mutant)
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-ZN:
Unknown entry

ChemComp-LCJ:
5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
  • spodoptera exigua (beet armyworm)
KeywordsTRANSFERASE / CRAF-MEK1-14-3-3 complex / MAPK pathway

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