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Tetrameric oligomerization of I kappa B kinase gamma (IKK gamma) is obligatory for IKK complex activity and NF-kappa B activation

Authors

  • S. Tegethoff
  • J. Behlke
  • C. Scheidereit

Journal

  • Molecular and Cellular Biology

Citation

  • Mol Cell Biol 23 (6): 2029-2041

Abstract

  • The IκB kinase (IKK) complex mediates activation of transcription factor NF-κB by phosphorylation of IκB proteins. Its catalytic subunits, IKK{alpha} and IKK{beta}, require association with the regulatory IKKγ (NEMO) component to gain full basal and inducible kinase activity. However, the oligomeric composition of the IKK complex and its regulation by IKK{gamma} are poorly understood. We show here that IKKγ predominantly forms tetramers and interacts with IKK{alpha} or IKK{beta} 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 IKKγ 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 IKK{beta} and IKK{gamma}, although the kinase can still interact with the resultant IKKγ monomers and dimers. Likewise, MOD-mediated IKKγ tetramerization is required to enhance IKK{beta} kinase activity when overexpressed in 293 cells and to reconstitute a lipopolysaccharide-responsive IKK complex in pre-B cells. These data thus suggest that IKKγ tetramerization enforces a spatial positioning of two kinase dimers to facilitate transautophosphorylation and activation.


DOI

doi:10.1128/MCB.23.6.2029-2041.2003