Open AccessA Central Region of NF-κB Essential Modulator Is Required for IKKβ-Induced Conformational Change and for Signal Propagation
Author(s) -
Robert Shaffer,
Anthony M. DeMaria,
Larisa Kagermazova,
Yuekun Liu,
Milad Babaei,
Suhaily Caban-Penix,
Arisdelsy Cervantes,
Stefan Jehle,
Lee Makowski,
Thomas D. Gilmore,
Adrian Whitty,
Karen N. Allen
Publication year - 2019
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.8b01316
Subject(s) - iκb kinase , conformational change , nf κb , signal (programming language) , chemistry , modulation (music) , signal transduction , signal pathway , biophysics , microbiology and biotechnology , physics , biology , biochemistry , computer science , acoustics , programming language
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 a molecular explanation for certain disease-associated mutations within the IVD and provide insight into the role of conformational change in signaling scaffold proteins.