Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

Angewandte Chemie - International Edition - Tập 55 Số 3 - Trang 983-986 - 2016
Pablo G. Jambrina1,2, Nora Rauch3,2, Ruth Pilkington3, Katja N. Rybakova3, Lan K. Nguyen4,5, Boris Ν. Kholodenko3, Nicolae‐Viorel Buchete6, Walter Kölch7,3, Edina Rosta1
1Department of Chemistry, King's College London, London SE1 1DB, UK
2these authors contributed equally to this work
3Systems Biology Ireland and Conway Institute, University College Dublin, Belfield, Dublin, 4 Ireland
4Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, 3800 Australia
5Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland,
6School of Physics and Complex and Adaptative Systems Laboratory, University College Dublin, Belfield, Dublin, 4 Ireland
7School of Medicine & Medical Sciences University College Dublin, Belfield Dublin 4 Ireland

Tóm tắt

AbstractRAF 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.

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Angewandte Chemie - International Edition

Tập 55 Số 3

983-986

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