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 path...

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Vydané v:	Nature communications Ročník 15; číslo 1; s. 7692 - 19
Hlavní autori:	Li, Changqing, Moro, Stefano, Shostak, Kateryna, O’Reilly, Francis J., Donzeau, Mariel, Graziadei, Andrea, McEwen, Alastair G., Desplancq, Dominique, Poussin-Courmontagne, Pierre, Bachelart, Thomas, Fiskin, Mert, Berrodier, Nicolas, Pichard, Simon, Brillet, Karl, Orfanoudakis, Georges, Poterszman, Arnaud, Torbeev, Vladimir, Rappsilber, Juri, Davey, Norman E., Chariot, Alain, Zanier, Katia
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 03.09.2024 Nature Publishing Group Springer Science and Business Media LLC Nature Portfolio
Predmet:	101/58 14 38 631/250/516/1909 631/45/275 631/535/1266 82/80 82/83 96 96/35 96/95 Amino Acid Motifs Biochemistry, biophysics & molecular biology Biochimie, biophysique & biologie moléculaire Dimerization Dimers Docking Enzyme inhibitors Gene expression Grooves HEK293 Cells Humanities and Social Sciences Humans I-kappa B Kinase I-kappa B Kinase - chemistry I-kappa B Kinase - genetics I-kappa B Kinase - metabolism IKK protein Kinases Life Sciences Molecular Docking Simulation Molecular modelling multidisciplinary NF-kappa B NF-kappa B - metabolism NF-KappaB Inhibitor alpha NF-KappaB Inhibitor alpha - genetics NF-KappaB Inhibitor alpha - metabolism NF-κB protein Phosphorylation Protein Binding Protein Multimerization Science Science (multidisciplinary) Sciences du vivant Signal Transduction Substrate inhibition Substrate Specificity Substrates Tyrosine
ISSN:	2041-1723, 2041-1723
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 scopus-id:2-s2.0-85202994520
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-52076-0