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Papers In Press, published online ahead of print October 23, 2002
J. Biol. Chem, 10.1074/jbc.M207515200
Submitted on July 25, 2002
Revised on October 22, 2002
Accepted on October 23, 2002

p105/Ikappa Bgamma and prototypical Ikappa Bs use a similar mechanism to bind but a different mechanism to regulate the sub-cellular localization of NF-kappa B

Anu K Moorthy and Gourisankar Ghosh

Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093

Corresponding Author: gghosh{at}ucsd.edu

p105, also known as NF-kappa B1, is an atypical Ikappa B molecule with a multi-domain organization distinct from other prototypical Ikappa Bs, like Ikappa Balpha and Ikappa Bbeta . To understand the mechanism by which p105 binds and inhibits NF-kappa B, we have used both p105 and its C-terminal inhibitory segment known as Ikappa Bgamma , for our study. We show here that one Ikappa Bgamma molecule binds to NF-kappa B dimers wherein at least one NF-kappa B subunit is p50. We suggest that the obligatory p50 subunit in Ikappa Bgamma /NF-kappa B complexes is equivalent to the N-terminal p50 segment in all p105/NF-kappa B complexes. The NLS of the obligatory p50 subunit is masked by Ikappa Bgamma whereas the NLS of the non-obligatory NF-kappa B subunit is exposed. Thus, the global binding mode of all Ikappa B/NF-kappa B complexes seems to be similar where one obligatory (or specific) NF-kappa B subunit makes intimate contact with Ikappa B and the non-obligatory (or non-specific) subunit is bound primarily through its ability to dimerize. In the case of Ikappa Balpha and Ikappa Bbeta the specific NF-kappa B subunit in the complex is p65. In contrast to Ikappa Balpha /NF-kappa B complexes, where the exposed NLS of the non-specific subunit imports the complex to the nucleus, p105/NF-kappa B or Ikappa Bgamma /NF-kappa B complexes are cytoplasmic. We show that the death domain of p105 (also of Ikappa Bgamma ) is essential for the cytoplasmic sequestration of NF-kappa B by p105 and Ikappa Bgamma . However, the death domain does not mask the exposed NLS of the complex. We also demonstrate that the death domain alone is not sufficient for cytoplasmic retention, and instead functions only in conjunction with other parts in the three-dimensional scaffold formed by the association of the ankyrin-repeat domain and NF-kappa B dimer. We speculate that additional cytoplasmic protein(s) may sequester the entire p105/NF-kappa B complex by binding through the death domain and other segments, including the exposed NLS.


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