A Central Region of NF-κB Essential Modulator Is Required for IKKβ-Induced Conformational Change and for Signal Propagation
| Autor: | Anthony M. DeMaria, Thomas D. Gilmore, Suhaily Caban-Penix, Milad Babaei, Stefan Jehle, Robert Shaffer, Larisa Kagermazova, Yuekun Liu, Arisdelsy Cervantes, Adrian Whitty, Karen N. Allen, Lee Makowski |
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| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
congenital hereditary and neonatal diseases and abnormalities 0303 health sciences Conformational change Kinase 030302 biochemistry & molecular biology Wild type NF-κB Biochemistry Cell biology Amino acid 03 medical and health sciences chemistry.chemical_compound IκBα chemistry Phosphorylation skin and connective tissue diseases Binding domain |
| Zdroj: | Biochemistry. 58:2906-2920 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.8b01316 |
| Popis: | NF-κB essential modulator (NEMO) regulates NF-κB signaling by acting as a scaffold for the kinase IKKβ to direct its activity toward the NF-κB inhibitor, IκBα. Here, we show that a highly conserved central region of NEMO termed the intervening domain (IVD, amino acids 112–195) plays a key role in NEMO function. We determined a structural model of full-length NEMO by small-angle X-ray scattering and show that full-length, wild-type NEMO becomes more compact upon binding of a peptide comprising the NEMO binding domain of IKKβ (amino acids 701–745). Mutation of conserved IVD residues (9SG-NEMO) disrupts this conformational change in NEMO and abolishes the ability of NEMO to propagate NF-κB signaling in cells, although the affinity of 9SG-NEMO for IKKβ compared to that of the wild type is unchanged. On the basis of these results, we propose a model in which the IVD is required for a conformational change in NEMO that is necessary for its ability to direct phosphorylation of IκBα by IKKβ. Our findings suggest ... |
| Databáze: | OpenAIRE |
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