1. Molecular mechanism of IKK catalytic dimer docking to NF-κB substrates.
- Author
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Li C, Moro S, Shostak K, O'Reilly FJ, Donzeau M, Graziadei A, McEwen AG, Desplancq D, Poussin-Courmontagne P, Bachelart T, Fiskin M, Berrodier N, Pichard S, Brillet K, Orfanoudakis G, Poterszman A, Torbeev V, Rappsilber J, Davey NE, Chariot A, and Zanier K
- Subjects
- Humans, Phosphorylation, Protein Binding, Signal Transduction, NF-KappaB Inhibitor alpha metabolism, NF-KappaB Inhibitor alpha genetics, Molecular Docking Simulation, HEK293 Cells, Substrate Specificity, I-kappa B Kinase metabolism, I-kappa B Kinase chemistry, I-kappa B Kinase genetics, NF-kappa B metabolism, Protein Multimerization, Amino Acid Motifs
- 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., (© 2024. The Author(s).)
- Published
- 2024
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