Biotechnology and Cell Signaling (CNRS/Université de Strasbourg, UMR7242), Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, 67400, Illkirch, France.
Laboratory of Cancer Biology, GIGA Cancer, University of Liege, CHU, Sart-Tilman, 4000, Liege, Belgium.
Nat Commun. 2024 Sep 3;15(1):7692. doi: 10.1038/s41467-024-52076-0.
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.
抑制κB（IκB）激酶（IKK）是 NF-κB 信号转导的核心调节剂。所有 IKK 复合物都包含催化 IKKβ和/或 IKKα亚基的异源或同源二聚体。在这里，我们鉴定了一个 YDDΦxΦ 基序，该基序在经典（IκBα、IκBβ）和替代（p100）NF-κB 途径的底物中保守，并介导与催化 IKK 二聚体的对接。我们证明了对接亲和力与与 IκBα磷酸化/降解相关的 IKK 活性之间存在定量相关性。此外，我们表明该基序保守酪氨酸的磷酸化，先前报道该事件可促进 IκBα积累并抑制 NF-κB 基因表达，可抑制对接相互作用。综合结构分析的结果表明，该基序与 IKK 二聚体界面上的凹槽结合。一致地，抑制 IKK 二聚化也会破坏 IκBα底物结合。最后，我们表明优化的二价基序肽可抑制 NF-κB 信号转导。这项工作揭示了 IKKα/β二聚体在底物基序识别中的作用。
