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Mol Cell Biol. 2003 Mar;23(6):2029-41.

Tetrameric oligomerization of IkappaB kinase gamma (IKKgamma) is obligatory for IKK complex activity and NF-kappaB activation.

Author information

  • 1Cell Growth and Differentiation Program, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.

Abstract

The IkappaB kinase (IKK) complex mediates activation of transcription factor NF-kappaB by phosphorylation of IkappaB proteins. Its catalytic subunits, IKKalpha and IKKbeta, require association with the regulatory IKKgamma (NEMO) component to gain full basal and inducible kinase activity. However, the oligomeric composition of the IKK complex and its regulation by IKKgamma are poorly understood. We show here that IKKgamma predominantly forms tetramers and interacts with IKKalpha or IKKbeta in this state. We propose that tetramerization is accomplished by a prerequisite dimerization through a C-terminal coiled-coil minimal oligomerization domain (MOD). This is followed by dimerization of the dimers with their N-terminal sequences. Tetrameric IKKgamma sequesters four kinase molecules, yielding a gamma(4)(alpha/beta)(4) stoichiometry. Deletion of the MOD leads to loss of tetramerization and of phosphorylation of IKKbeta and IKKgamma, although the kinase can still interact with the resultant IKKgamma monomers and dimers. Likewise, MOD-mediated IKKgamma tetramerization is required to enhance IKKbeta kinase activity when overexpressed in 293 cells and to reconstitute a lipopolysaccharide-responsive IKK complex in pre-B cells. These data thus suggest that IKKgamma tetramerization enforces a spatial positioning of two kinase dimers to facilitate transautophosphorylation and activation.

PMID:
12612076
[PubMed - indexed for MEDLINE]
PMCID:
PMC149477
Free PMC Article

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