Fig. 6 Perturbation of tetrameric RAS:RAF complexes in intact cells.

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Fig. 6 Perturbation of tetrameric RAS:RAF complexes in intact cells. Perturbation of tetrameric RAS:RAF complexes in intact cells. (A) Illustration of strategies on how to interfere with tetrameric RAS:RAF complexes. (B) Structure illustration indicates the localization of W75 and W77 in the RAS:NS1 binding interface (PDB: 5E95). (C) Localization study of YFP-tagged NS1 and NS1neg in the absence or presence of HA-HRAS in HEK293 cells. Scale bars, 25 μm. RAF dimerization analyses using indicated PPI reporters, NS1 variants, and upon coexpression of HRAS variants (n = 3; ±SEM). (D) RAF dimerization analyses using indicated PPI reporter constructs and coexpression of HRAS variants (n = 3; ±SEM). (E) PPI reporter analyses of transiently expressed reporter protein pairs with and without indicated HRAS variants and following 1-hour treatment with PLX8394. Quantifications from n = 5 independent experiments are shown (±SEM). (F) IP of flag-tagged HRASG12V in the presence of wild-type and RAS-binding deficient (R88A) CRAF-NanoLuc (NL) variants from BRAF-V600E–positive melanoma cells A375. The PKA RI subunit serves as unrelated prey. Quantifications from n = 4 independent experiments are shown (±SEM). Student’s t test was used to evaluate statistical significance. Confidence levels: *P < 0.05, **P < 0.01, and ***P < 0.001. (G) Systematic analyses using the full-length BRAF reporter platform unveiled the sequence of reorganizations of macromolecular kinase complexes upon αC-OUT BRAFi binding to the catalytic kinase pocket of mutated BRAF (left protomer, e.g., V600E mutation = *). Dose-dependent αC-OUT BRAFi binding to mutant BRAF promotes intermediate RAF conformations (1), thereby elevating BRAF*:RASGTP interactions (2) and endorsing the formation of RAS nanocluster/dimer–organized RASGTP:BRAF*:RAF:RASGTP tetramers (3), which may lead to the activation of a complexed second RAF protomer (4). RAS-specific monobodies and RBD:RAS interface mutations counteract BRAFi-promoted RAS:RAF complexes. Ruth Röck et al. Sci Adv 2019;5:eaav8463 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).