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Molecular and Cellular Biology, March 2003, p. 2029-2041, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.2029-2041.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Tetrameric Oligomerization of I{kappa}B Kinase {gamma} (IKK{gamma}) Is Obligatory for IKK Complex Activity and NF-{kappa}B Activation

Sebastian Tegethoff, Joachim Behlke, and Claus Scheidereit*

Max Delbrück Center for Molecular Medicine, 13092 Berlin, Germany

Received 9 September 2002/ Returned for modification 23 October 2002/ Accepted 19 December 2002

The I{kappa}B kinase (IKK) complex mediates activation of transcription factor NF-{kappa}B by phosphorylation of I{kappa}B proteins. Its catalytic subunits, IKK{alpha} and IKKß, require association with the regulatory IKK{gamma} (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 IKK{gamma} predominantly forms tetramers and interacts with IKK{alpha} or IKKß 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 IKK{gamma} sequesters four kinase molecules, yielding a {gamma}4({alpha}/ß)4 stoichiometry. Deletion of the MOD leads to loss of tetramerization and of phosphorylation of IKKß and IKK{gamma}, although the kinase can still interact with the resultant IKK{gamma} monomers and dimers. Likewise, MOD-mediated IKK{gamma} tetramerization is required to enhance IKKß kinase activity when overexpressed in 293 cells and to reconstitute a lipopolysaccharide-responsive IKK complex in pre-B cells. These data thus suggest that IKK{gamma} tetramerization enforces a spatial positioning of two kinase dimers to facilitate transautophosphorylation and activation.

* Corresponding author. Mailing address: Max Delbrück Center for Molecular Medicine, Cell Growth and Differentiation Program, Robert-Rössle-Str. 10, 13122 Berlin, Germany. Phone: 49-30-9406-3816. Fax: 49-30-9406-3866. E-mail: scheidereit{at}mdc-berlin.de.

Molecular and Cellular Biology, March 2003, p. 2029-2041, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.2029-2041.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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