e_re387

Reaction state_transition e_re387 map

GTP:​RAF1|​S259_pho|​S621_pho|​S_pho|​open:​YWHAB@Cytoplasm map + ATP@Cytoplasm map RAF1|​S259_pho|​S621_pho|​Y340_pho|​Y341_pho|​open@Cytoplasm map + ADP@Cytoplasm map

Reaction regulators:

Unknown_catalysis
  1. c-SRC*|​Y_pho|​active@Cytoplasm map



References
PMID:9069260
Activated HRAS (GTP bound forn) is associated with the plasma membrane.
Inactive RAF1 is associated in the cytoplasm with YWHAB via S259 phosphorylation site and also binding site.
RAF1 has a RAS-binding Cysteine-rich domain (CRD) and an additional RAS-binding domain (RBD).
RAF1 binds activated HRAS via the RBD. This binding displaces YWHAB from Ser259 and unmasks the CRD.
YWHAB has been displaced from S259 may now bind its higher affinity S621 site.
This stabilises an OPEN RAF1 conformation that is catalytically active.
Active and open RAF1 binds to RAS via both CRD and RBD domains.
An unidentified protein tyrosine kinase located in the plasma membrane phosphorylates tyrosine residues at 340 and 341.
This Tyrosine phosphorylation serves to further stabilise the active OPEN RAF1 conformation.
While the kinase has not been definitively identified, SRC is a plausible candidate. RAF1 interacts with SRC and co-immunoprecipates with SRC-FYN.
PIN1, a prolyl isomerase converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A.
Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: S338, Y374 and T491

Confidence
REF=0 FUNC=4


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