Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates
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.
Authors
- Mert Fiskin
- Katia Zanier (ORCID: https://orcid.org/0000-0002-7183-7356)
- Andrea Graziadei (ORCID: https://orcid.org/0000-0001-7709-6002)
- Karl Brillet (ORCID: https://orcid.org/0000-0002-7900-8923)
- Pierre Poussin‐Courmontagne (ORCID: https://orcid.org/0000-0003-4813-6882)
- Kateryna Shostak (ORCID: https://orcid.org/0000-0002-9946-3536)
- Simon Pichard (ORCID: https://orcid.org/0009-0008-9765-4006)
- Alastair G. McEwen (ORCID: https://orcid.org/0000-0003-4484-3512)
- Thomas Bachelart
- Dominique Desplancq
- Francis J. O’Reilly (ORCID: https://orcid.org/0000-0001-9258-0150)
- Stefano Moro
- Arnaud Poterszman (ORCID: https://orcid.org/0000-0002-6702-5777)
- Juri Rappsilber (ORCID: https://orcid.org/0000-0001-5999-1310)
- Alain Chariot (ORCID: https://orcid.org/0000-0002-1691-4347)
- Georges Orfanoudakis (ORCID: https://orcid.org/0000-0002-0064-1305)
- Norman E. Davey (ORCID: https://orcid.org/0000-0001-6988-4850)
- Vladimir Torbeev (ORCID: https://orcid.org/0000-0002-7865-1044)
- Changqing Li (ORCID: https://orcid.org/0000-0003-4380-2284)
- Mariel Donzeau (ORCID: https://orcid.org/0000-0002-1145-9218)
- Nicolas Berrodier
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institute of Cancer Research (GB)
- Inserm (FR)
- University of Liège (BE)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Walloon Excellence in Lifesciences and Biotechnology (BE)
- Biotechnologie et Signalisation Cellulaire (FR)
- Institut de Biologie Moléculaire et Cellulaire (FR)
- Technische Universität Berlin (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-03
- DOI
- https://doi.org/10.1038/s41467-024-52076-0
- Citations
- 25
- Primary Topic
- NF-κB Signaling Pathways
- Type
- article
- Field-Weighted Citation Impact
- 7.13
Funders
- International Business Machines Corporation
- Universität Heidelberg
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Université de Strasbourg
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- French Infrastructure for Integrated Structural Biology