Fiche publication
Date publication
septembre 2024
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ORFANOUDAKIS Georges
,
Dr POTERSZMAN Arnaud
,
Dr ZANIER Katia
,
Dr DONZEAU Mariel
Tous les auteurs :
Li C, Moro S, Shostak K, O'Reilly FJ, Donzeau M, Graziadei A, McEwen AG, Desplancq D, Poussin-Courmontagne P, Bachelart T, Fiskin M, Berrodier N, Pichard S, Brillet K, Orfanoudakis G, Poterszman A, Torbeev V, Rappsilber J, Davey NE, Chariot A, Zanier K
Lien Pubmed
Résumé
The inhibitor of κB (IκB) kinase (IKK) is a central regulator of NF-κB signaling. All IKK complexes contain hetero- or homodimers of the catalytic IKKβ and/or IKKα subunits. Here, we identify a YDDΦxΦ motif, which is conserved in substrates of canonical (IκBα, IκBβ) and alternative (p100) NF-κB pathways, and which mediates docking to catalytic IKK dimers. We demonstrate a quantitative correlation between docking affinity and IKK activity related to IκBα phosphorylation/degradation. Furthermore, we show that phosphorylation of the motif's conserved tyrosine, an event previously reported to promote IκBα accumulation and inhibition of NF-κB gene expression, suppresses the docking interaction. Results from integrated structural analyzes indicate that the motif binds to a groove at the IKK dimer interface. Consistently, suppression of IKK dimerization also abolishes IκBα substrate binding. Finally, we show that an optimized bivalent motif peptide inhibits NF-κB signaling. This work unveils a function for IKKα/β dimerization in substrate motif recognition.
Mots clés
I-kappa B Kinase, metabolism, Humans, NF-kappa B, metabolism, Phosphorylation, Protein Multimerization, Amino Acid Motifs, Protein Binding, Signal Transduction, NF-KappaB Inhibitor alpha, metabolism, Molecular Docking Simulation, HEK293 Cells, Substrate Specificity
Référence
Nat Commun. 2024 09 3;15(1):7692
