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Mol Cell Biol, May 1998, p. 2640-2649, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The N-Terminal Domain of Ikappa Balpha Masks the Nuclear Localization Signal(s) of p50 and c-Rel Homodimers

Matthew Latimer, Mary K. Ernst, Linda L. Dunn, Marina Drutskaya, and Nancy R. Rice*

Molecular Basis of Carcinogenesis Laboratory, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21701

Received 14 October 1997/Returned for modification 3 December 1997/Accepted 20 February 1998

Members of the Rel/NF-kappa B family of transcription factors are related to each other over a region of about 300 amino acids called the Rel Homology Domain (RHD), which governs DNA binding, dimerization, and binding to inhibitor. At the C-terminal end of the RHD, each protein has a nuclear localization signal (NLS). The crystal structures of the p50 and RelA family members show that the RHD consists of two regions: an N-terminal section which contains some of the DNA contacts and a C-terminal section which contains the remaining DNA contacts and controls dimerization. In unstimulated cells, the homo- or heterodimeric Rel/NF-kappa B proteins are cytoplasmic by virtue of binding to an inhibitor protein (Ikappa B) which somehow masks the NLS of each member of the dimer. The Ikappa B proteins consist of an ankyrin-repeat-containing domain that is required for binding to dimers and N- and C-terminal domains that are dispensable for binding to most dimers. In this study, we examined the interaction between Ikappa Balpha and Rel family homodimers by mutational analysis. We show that (i) the dimerization regions of p50, RelA, and c-Rel are sufficient for binding to Ikappa Balpha , (ii) the NLSs of RelA and c-Rel are not required for binding to Ikappa Balpha but do stabilize the interaction, (iii) the NLS of p50 is required for binding to Ikappa Balpha , (iv) only certain residues within the p50 NLS are required for binding, and (v) in a p50-Ikappa Balpha complex or a c-Rel-Ikappa Balpha complex, the N terminus of Ikappa Balpha either directly or indirectly masks one or both of the dimer NLSs.

* Corresponding author. Mailing address: Molecular Basis of Carcinogenesis Lab., ABL-Basic Research Program, NCI-Frederick Cancer Res. and Development Center, P.O. Box B, Frederick, MD 21702-1201. Phone: (301) 846-1360. Fax: (301) 846-1666.

Mol Cell Biol, May 1998, p. 2640-2649, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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