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. 2021 Feb 19;12:1176. doi: 10.1038/s41467-021-21422-x

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021

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Fig. 8 — a Structural superposition of KRAS-RBDCRD and the cryoEM structure of MEK-BRAF-14-3-3 (PDB 6NYB). Structures were aligned by their CRD domains. KRAS is hidden in this panel in order to show the alignment of CRD and the placement of RBD clearly. RAF1(RBDCRD) has the same color-coding scheme as used in Fig. 1c, while MEK, BRAF, and 14-3-3 are colored light blue, brown, and gray, respectively. b Same as a but at a different angle. KRAS is shown to illustrate it has minimal contacts with 14-3-3 in our structural alignment based on CRD. c Schematic diagram showing KRAS first interacts with autoinhibited RAF via RBD and then CRD to bring RAF close to the membrane. This results in CRD coming out of the autoinhibited conformation and interacting with the membrane and KRAS, and in turn exposing the phosphorylated serine present in the CR2 region. Dephosphorylation of S259 (RAF1) by SHOC2 complex results in an active RAF1 monomer, where 14-3-3 binds to only one phosphorylated serine located at the C-terminal end. Homo-dimerization or hetero-dimerization of KRAS-RAF1 with an active RAF monomer containing either RAF1 or BRAF results in the formation of an active dimerized RAF complex. RAF1 has been shown to prefer hetero-dimerization with BRAF which is bound to MEK for initiating the activation cascade.