Allosteric activation of RAF in the MAPK signaling pathway. (December 2018)

• Record Type: Journal Article
• Authors: Tsai, Chung-Jung; Nussinov, Ruth
• Is Part Of: Current opinion in structural biology. Volume 53(2018)
• Page Start: 100
• Page End: 106
• Publication Date: 2018-12
• Subjects: Molecular biology -- Periodicals; 570
• DOI: 10.1016/j.sbi.2018.07.007
• Languages: English
• ISSNs: 0959-440X

Abstract

Highlights: Physiologically, kinases populate the inactive state; stimuli shift the population. In cancer, kinases constitutively populate the active state. Physiologically, RAF's activation requires its RAS-dependent dimerization. We explain why dimerization is required, and how the V600E mutation activates RAF. We also explain RAF's paradoxical activation, all from the allosteric standpoint. Abstract : Protein kinases are evolutionarily crafted into two functional states. In response to stimuli, kinase, which is usually populated in an inactive state, becomes active. Here, we outline a unified scheme to explain how kinases are activated physiologically and pathologically, focusing on RAF allosteric activation. Key concepts include the population shift from the inactive to the active state is relative ; the relative populations are altered additively via allosteric events; and the structural features of the active conformation are coupled with the regulatory and catalytic spines to align the catalytic sequence motifs. This structural insight clarifies why the prerequisite of RAF dimerization, how the V600E oncogenic mutation activates RAF, how a RAF inhibitor executes paradoxical activation, and provides pharmaceutical guidelines.