8omv
Crystal structure of the constitutively active S117E/S181E mutant of human IKK2
Structural highlights
FunctionIKKB_HUMAN Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe inhibitor of kappaB (IkappaB) kinase (IKK) is a central regulator of NF-kappaB signaling. All IKK complexes contain hetero- or homodimers of the catalytic IKKbeta and/or IKKalpha subunits. Here, we identify a YDDPhixPhi motif, which is conserved in substrates of canonical (IkappaBalpha, IkappaBbeta) and alternative (p100) NF-kappaB pathways, and which mediates docking to catalytic IKK dimers. We demonstrate a quantitative correlation between docking affinity and IKK activity related to IkappaBalpha phosphorylation/degradation. Furthermore, we show that phosphorylation of the motif's conserved tyrosine, an event previously reported to promote IkappaBalpha accumulation and inhibition of NF-kappaB 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 IkappaBalpha substrate binding. Finally, we show that an optimized bivalent motif peptide inhibits NF-kappaB signaling. This work unveils a function for IKKalpha/beta dimerization in substrate motif recognition. Molecular mechanism of IKK catalytic dimer docking to NF-kappaB substrates.,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, Zanier K Nat Commun. 2024 Sep 3;15(1):7692. doi: 10.1038/s41467-024-52076-0. PMID:39227404[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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