8OMV

Crystal structure of the constitutively active S117E/S181E mutant of human IKK2

Summary for 8OMV

• Entry DOI: 10.2210/pdb8omv/pdb
• Descriptor: Inhibitor of nuclear factor kappa-B kinase subunit beta (1 entity in total)
• Functional Keywords: ikk, nf-kappab, ikba, docking, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 5
• Total formula weight: 387043.91

Authors

McEwen, A.G.,Li, C.,Moro, S.,Poussin-Courmontagne, P.,Zanier, K. (deposition date: 2023-03-31, release date: 2024-04-10, Last modification date: 2024-10-23)

Primary citation

Li, C.,Moro, S.,Shostak, K.,O'Reilly, F.J.,Donzeau, M.,Graziadei, A.,McEwen, A.G.,Desplancq, D.,Poussin-Courmontagne, P.,Bachelart, T.,Fiskin, M.,Berrodier, N.,Pichard, S.,Brillet, K.,Orfanoudakis, G.,Poterszman, A.,Torbeev, V.,Rappsilber, J.,Davey, N.E.,Chariot, A.,Zanier, K.
Molecular mechanism of IKK catalytic dimer docking to NF-kappa B substrates.
Nat Commun, 15:7692-7692, 2024

PubMed 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.

PubMed: 39227404
DOI: 10.1038/s41467-024-52076-0

Experimental method

X-RAY DIFFRACTION (4.16 Å)