Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

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Title: Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
Authors: Jambrina, Pablo G.
Rauch, Nora
Pilkington, Ruth
Rybakova, Katja
Nguyen, Lan K.
Kholodenko, Boris N.
Buchete, Nicolae-Viorel
Kolch, Walter
Rosta, Edina
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Date: 8-Dec-2015
Online since: 2019-04-02T11:59:40Z
Abstract: RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N-terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the αC-helix and charged residues upstream of the NtA motif. Additionally, we show that the R-spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure-based mechanism for the auto-transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization-related drug resistance.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
Type of material: Journal Article
Publisher: Wiley
Journal: Angewandte Chemie
Volume: 55
Issue: 3
Start page: 983
End page: 986
Copyright (published version): 2015 the Authors
Keywords: RAF kinaseKinasesMolecular dynamicsOncogenic signalingPhosophorylation
DOI: 10.1002/anie.201509272
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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