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• W4384264009 abstract "BRAF is a key member in the MAPK signaling pathway essential for cell growth, proliferation, and differentiation. Dysregulation or mutation of BRAF is often the underlying cause of various types of cancer. RAS, a small GTPase protein that acts upstream of BRAF, has been identified as a driver of up to one-third of all cancers. When BRAF interacts with RAS via the RAS binding domain (RBD) and membrane recruitment, BRAF undergoes a conformational change from an inactive, autoinhibited monomer to an active dimer and subsequently phosphorylates MEK to propagate the signal. BRAF domains are involved in specific functions of the regulatory mechanism, as exampled by maintenance of the autoinhibited conformation through interactions between the Cysteine Rich Domain (CRD) and the Kinase Domain (KD) of BRAF. Despite the central role of BRAF in cellular signaling, the exact order and magnitude of its activation steps has yet to be confirmed experimentally. We employed pulldown assays, open surface plasmon resonance (OpenSPR), and hydrogen-deuterium exchange mass spectrometry (HDX-MS) to investigate the roles of the regulatory regions in BRAF activation and autoinhibition. Our results demonstrate that the BRAF specific region (BSR) and CRD play a crucial role in regulating the activity of BRAF. Moreover, we quantified the autoinhibitory binding affinities between the N-terminal domains of BRAF and the KD and revealed the individual roles of the BRAF regulatory domains. Furthermore, we quantified the relief of autoinhibition between the N-terminal domains of BRAF and the KD upon RAS binding, providing direct evidence that RAS binding initiates RAF activation. Additionally, our findings provide evidence that the BSR negatively regulates BRAF activation in a RAS isoform-specific manner and highlight the importance of considering the specific isoform pairs when developing inhibitors targeting RAF-RAS interactions. Our findings also indicate that oncogenic BRAF-KDD594G mutant has a lower affinity for the regulatory domains, implicating that pathogenic BRAF acts through decreased propensity for autoinhibition. Collectively, our study provides valuable insights into the activation mechanism of BRAF kinase and may help to guide the development of new therapeutic strategies for cancer treatment." @default.
• W4384264009 created "2023-07-14" @default.
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• W4384264009 date "2023-07-13" @default.
• W4384264009 modified "2023-09-23" @default.
• W4384264009 title "Unveiling the Domain-Specific and RAS Isoform-Specific Details of BRAF Regulation" @default.
• W4384264009 doi "https://doi.org/10.7554/elife.88836" @default.
• W4384264009 hasPublicationYear "2023" @default.
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