Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates
Changqing Li, Stefano Moro, Kateryna Shostak, Francis J. O’Reilly, Mariel Donzeau, Andrea Graziadei, Alastair G. McEwen, Dominique Desplancq, Pierre Poussin‐Courmontagne, Thomas Bachelart, Mert Fiskin, Nicolas Berrodier, Simon Pichard, Karl Brillet, Georges Orfanoudakis, Arnaud Poterszman, Vladimir Torbeev, Juri Rappsilber, Norman E. Davey, Alain Chariot, Katia Zanier
Abstract
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. The inhibitor of kB kinase (IKK) is a central regulator of NF-kB signalling. Here the authors identify a motif conserved in substrates of canonical and alternative NF-kB pathways which mediates docking to catalytic IKK dimers: they show that phosphorylation of the conserved tyrosine suppresses the docking interaction.