Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates.

Autor: Li C; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Moro S; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Shostak K; Laboratory of Cancer Biology, GIGA Cancer, University of Liege, CHU, Sart-Tilman, 4000, Liege, Belgium., O'Reilly FJ; Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, Berlin, Germany., Donzeau M; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Graziadei A; Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, Berlin, Germany., McEwen AG; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg, 1 rue Laurent Fries, 67400, Illkirch, France., Desplancq D; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Poussin-Courmontagne P; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg, 1 rue Laurent Fries, 67400, Illkirch, France., Bachelart T; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Fiskin M; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Berrodier N; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg, 1 rue Laurent Fries, 67400, Illkirch, France., Pichard S; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg, 1 rue Laurent Fries, 67400, Illkirch, France., Brillet K; Institut Biologie Moléculaire et Cellulaire (IBMC), CNRS UPR9002, 2 allée Konrad Roentgen, 67000, Strasbourg, France., Orfanoudakis G; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Poterszman A; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) / INSERM UMR-S 1258 / CNRS UMR7104/ Université de Strasbourg, 1 rue Laurent Fries, 67400, Illkirch, France., Torbeev V; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France., Rappsilber J; Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, Berlin, Germany., Davey NE; Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK., Chariot A; Laboratory of Cancer Biology, GIGA Cancer, University of Liege, CHU, Sart-Tilman, 4000, Liege, Belgium.; WELBIO department, WEL Research Institute, avenue Pasteur, 6, 1300, Wavre, Belgium., Zanier K; Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France. zanier@unistra.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 03; Vol. 15 (1), pp. 7692. Date of Electronic Publication: 2024 Sep 03.
DOI: 10.1038/s41467-024-52076-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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