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.
Rushe
Mia
M
Biogen Idec Inc., Cambridge, MA 02142, USA.
Silvian
Laura
L
Bixler
Sarah
S
Chen
Ling Ling
LL
Cheung
Anne
A
Bowes
Scott
S
Cuervo
Hernan
H
Berkowitz
Steven
S
Zheng
Timothy
T
Guckian
Kevin
K
Pellegrini
Maria
M
Lugovskoy
Alexey
A
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
D051550:I-kappa B Kinase