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.
Nguyen, Lan K.
Kholodenko, Boris N.
|Permanent link:||http://hdl.handle.net/10197/9773||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 kinase; Kinases; Molecular dynamics; Oncogenic signaling; Phosophorylation||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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