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Analyses of the oncogenic BRAFD594G variant reveal a kinase-independent function of BRAF in activating MAPK signaling

The Journal of biological chemistry, 2020-02, Vol.295 (8), p.2407-2420 [Peer Reviewed Journal]

2020 © 2020 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2020 Cope et al. 2020 Cope et al. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.RA119.011536 ;PMID: 31929109

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  • Title:
    Analyses of the oncogenic BRAFD594G variant reveal a kinase-independent function of BRAF in activating MAPK signaling
  • Author: Cope, Nicholas J. ; Novak, Borna ; Liu, Zhiwei ; Cavallo, Maria ; Gunderwala, Amber Y. ; Connolly, Matthew ; Wang, Zhihong
  • Subjects: 14–3-3 protein ; allosteric activation ; allosteric inhibitor ; ATP ; ATP-competitive inhibitor ; autophosphorylation ; cancer ; DFG motif ; dimerization ; kinase signaling ; Molecular Bases of Disease ; molecular dynamics ; P-loop ; paradoxical activation ; peptide inhibitor ; phosphorylation ; protein kinase ; Raf kinase
  • Is Part Of: The Journal of biological chemistry, 2020-02, Vol.295 (8), p.2407-2420
  • Description: Class 3 mutations in B-Raf proto-oncogene, Ser/Thr kinase (BRAF), that result in kinase-impaired or kinase-dead BRAF have the highest mutation frequency in BRAF gene in lung adenocarcinoma. Several studies have reported that kinase-dead BRAF variants amplify mitogen-activated protein kinase (MAPK) signaling by dimerizing with and activating WT C-Raf proto-oncogene, Ser/Thr kinase (CRAF). However, the structural and functional principles underlying their activation remain elusive. Herein, using cell biology and various biochemical approaches, we established that variant BRAFD594G, a kinase-dead representative of class 3 mutation-derived BRAF variants, has a higher dimerization potential as compared with WT BRAF. Molecular dynamics simulations uncovered that the D594G substitution orients the αC-helix toward the IN position and extends the activation loop within the kinase domain, shifting the equilibrium toward the active, dimeric conformation, thus priming BRAFD594G as an effective allosteric activator of CRAF. We found that B/CRAF heterodimers are the most thermodynamically stable RAF dimers, suggesting that RAF heterodimers, and not homodimers, are the major players in determining the amplitude of MAPK signaling in cells. Additionally, we show that BRAFD594G:CRAF heterodimers bypass autoinhibitory P-loop phosphorylation, which might contribute to longer duration of MAPK pathway signaling in cancer cells. Last, we propose that the dimer interface of the BRAFD594G:CRAF heterodimer may represent a promising target in the design of novel anticancer therapeutics.
  • Publisher: 11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 0021-9258
    EISSN: 1083-351X
    DOI: 10.1074/jbc.RA119.011536
    PMID: 31929109
  • Source: PubMed Central
    Alma/SFX Local Collection
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