Structure of a NEMO/IKK-Associating Domain Reveals Architecture of the Interaction Site

• DOI: 10.1016/j.str.2008.02.012
• Publication Date: 2008-05-07T14:16:15Z
• Authors: Mia Rushe; Laura Silvian; Sarah Bixler; Ling Ling Chen; Anne Cheung; Scott Bowes; Hernan Cuervo; Steven Berkowitz; Timothy Zheng; Kevin Guckian; Maria Pellegrini; Alexey Lugovskoy
• Keywords: Inclusion Bodies; Models, Molecular; Protein Folding; 0303 health sciences; Binding Sites; Sequence Homology, Amino Acid; PROTEINS; Protein Conformation; Molecular Sequence Data; Biophysics; Spectrum Analysis, Raman; I-kappa B Kinase; Protein Structure, Tertiary; 03 medical and health sciences; SIGNALING; Structural Biology; Escherichia coli; Humans; Amino Acid Sequence; Molecular Biology; Dimerization; Hydrophobic and Hydrophilic Interactions; Nuclear Magnetic Resonance, Biomolecular; Protein Binding

The phosphorylation of IkappaB by the IKK complex targets it for degradation and releases NF-kappaB for translocation into the nucleus to initiate the inflammatory response, cell proliferation, or cell differentiation. The IKK complex is composed of the catalytic IKKalpha/beta kinases and a regulatory protein, NF-kappaB essential modulator (NEMO; IKKgamma). NEMO associates with the unphosphorylated IKK kinase C termini and activates the IKK complex's catalytic activity. However, detailed structural information about the NEMO/IKK interaction is lacking. In this study, we have identified the minimal requirements for NEMO and IKK kinase association using a variety of biophysical techniques and have solved two crystal structures of the minimal NEMO/IKK kinase associating domains. We demonstrate that the NEMO core domain is a dimer that binds two IKK fragments and identify energetic hot spots that can be exploited to inhibit IKK complex formation with a therapeutic agent.