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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Published in:Nature communications Vol. 15; no. 1; pp. 7692 - 19
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 03.09.2024
Nature Publishing Group
Springer Science and Business Media LLC
Nature Portfolio
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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
Online Access:Get full text
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Summary: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.
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scopus-id:2-s2.0-85202994520
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-52076-0