Options
Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
Date Issued
2015-12-08
Date Available
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.
Sponsorship
European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
Other Sponsorship
Engineering and Physical Sciences Research Council (UK)
Biotechnology and Biological Sciences Research Council (UK)
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
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
File(s)
No Thumbnail Available
Name
PhosphorylationofRAFKinaseDimersDrivesConformational Changes KholodenkoB.pdf
Size
3.29 MB
Format
Owning collection
Scopus© citations
39
Acquisition Date
Mar 28, 2024
Mar 28, 2024
Views
834
Last Week
1
1
Last Month
3
3
Acquisition Date
Mar 28, 2024
Mar 28, 2024
Downloads
296
Last Week
2
2
Last Month
12
12
Acquisition Date
Mar 28, 2024
Mar 28, 2024