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 and Katia Zanier ()
Additional contact information
Changqing Li: Boulevard Sébastien Brant
Stefano Moro: Boulevard Sébastien Brant
Kateryna Shostak: CHU
Francis J. O’Reilly: Technische Universität Berlin
Mariel Donzeau: Boulevard Sébastien Brant
Andrea Graziadei: Technische Universität Berlin
Alastair G. McEwen: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg
Dominique Desplancq: Boulevard Sébastien Brant
Pierre Poussin-Courmontagne: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg
Thomas Bachelart: Boulevard Sébastien Brant
Mert Fiskin: Boulevard Sébastien Brant
Nicolas Berrodier: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg
Simon Pichard: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg
Karl Brillet: CNRS UPR9002
Georges Orfanoudakis: Boulevard Sébastien Brant
Arnaud Poterszman: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg
Vladimir Torbeev: Boulevard Sébastien Brant
Juri Rappsilber: Technische Universität Berlin
Norman E. Davey: The Institute of Cancer Research
Alain Chariot: CHU
Katia Zanier: Boulevard Sébastien Brant

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52076-0

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