Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site.
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.
Mesh Terms:
Amino Acid Sequence, Binding Sites, Biophysics, Dimerization, Escherichia coli, Humans, Hydrophobic and Hydrophilic Interactions, I-kappa B Kinase, Inclusion Bodies, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Spectrum Analysis, Raman
Amino Acid Sequence, Binding Sites, Biophysics, Dimerization, Escherichia coli, Humans, Hydrophobic and Hydrophilic Interactions, I-kappa B Kinase, Inclusion Bodies, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Sequence Homology, Amino Acid, Spectrum Analysis, Raman
Structure
Date: May. 01, 2008
PubMed ID: 18462684
View in: Pubmed Google Scholar
Download Curated Data For This Publication
207523
Switch View:
- Interactions 4