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. 2018 Dec 17;46(6):1393-1406.
doi: 10.1042/BST20170528. Epub 2018 Oct 31.

Structural Snapshots of RAF Kinase Interactions


Structural Snapshots of RAF Kinase Interactions

Soheila Rezaei Adariani et al. Biochem Soc Trans. .


RAF (rapidly accelerated fibrosarcoma) Ser/Thr kinases (ARAF, BRAF, and CRAF) link the RAS (rat sarcoma) protein family with the MAPK (mitogen-activated protein kinase) pathway and control cell growth, differentiation, development, aging, and tumorigenesis. Their activity is specifically modulated by protein-protein interactions, post-translational modifications, and conformational changes in specific spatiotemporal patterns via various upstream regulators, including the kinases, phosphatase, GTPases, and scaffold and modulator proteins. Dephosphorylation of Ser-259 (CRAF numbering) and dissociation of 14-3-3 release the RAF regulatory domains RAS-binding domain and cysteine-rich domain for interaction with RAS-GTP and membrane lipids. This, in turn, results in RAF phosphorylation at Ser-621 and 14-3-3 reassociation, followed by its dimerization and ultimately substrate binding and phosphorylation. This review focuses on structural understanding of how distinct binding partners trigger a cascade of molecular events that induces RAF kinase activation.

Keywords: 14-3-3 proteins; RAF kinases; RAS; RAS-binding domain; cysteine-rich domains; membrane lipids.

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