Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation

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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.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation ; volume:55 ; number:3 ; year:2016 ; pages:983-986 ; extent:4
Angewandte Chemie / International edition. International edition ; 55, Heft 3 (2016), 983-986 (gesamt 4)

Creator: Jambrina, Pablo G.
Rauch, Nora
Pilkington, Ruth
Rybakova, Katja
Nguyen, Lan K.
Kholodenko, Boris N.
Buchete, Nicolae‐Viorel
Kolch, Walter
Rosta, Edina

DOI: 10.1002/anie.201509272

URN: urn:nbn:de:101:1-2022110305363655119984

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 15.08.2025, 7:28 AM CEST

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Associated

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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