title: Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site.
abstract: 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.
authors.affiliation: Biogen Idec Inc., Cambridge, MA 02142, USA.
authors.forename: Mia
authors.initials: M
authors.lastname: Rushe
authors.forename: Laura
authors.initials: L
authors.lastname: Silvian
authors.forename: Sarah
authors.initials: S
authors.lastname: Bixler
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Chen
authors.forename: Anne
authors.initials: A
authors.lastname: Cheung
authors.forename: Scott
authors.initials: S
authors.lastname: Bowes
authors.forename: Hernan
authors.initials: H
authors.lastname: Cuervo
authors.forename: Steven
authors.initials: S
authors.lastname: Berkowitz
authors.forename: Timothy
authors.initials: T
authors.lastname: Zheng
authors.forename: Kevin
authors.initials: K
authors.lastname: Guckian
authors.forename: Maria
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Alexey
authors.initials: A
authors.lastname: Lugovskoy
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001703:Biophysics / Q000379:methods; D019281:Dimerization; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051550:I-kappa B Kinase / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D002479:Inclusion Bodies / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013059:Spectrum Analysis, Raman
chemical_list: D051550:I-kappa B Kinase