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J. Biol. Chem., Vol. 283, Issue 18, 12324-12332, May 2, 2008

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Stabilization of RelB Requires Multidomain Interactions with p100/p52^*

Amanda J. Fusco¹, Olga V. Savinova², Rashmi Talwar³, Jeffrey D. Kearns, Alexander Hoffmann, and Gourisankar Ghosh⁴

From the Department of Chemistry & Biochemistry and the Signaling Systems Laboratory, University of California, San Diego, La Jolla, California 92093

The NF-B family member RelB has many properties not shared by other family members such as restricted subunit association and lack of regulation by the classical IB proteins. We show that the protein level of RelB is significantly reduced in the absence of p100 and reduced even more when both p100 and p105 are absent. RelB stabilizes itself by directly interacting with p100, p105, and their processed products. However, RelB forms complexes with its partners using different interaction modes. Although the C-terminal ankyrin repeat domain of p105 is not involved in the RelB-p105 complex formation, all domains and flexible regions of each protein are engaged in the RelB-p100 complex. In several respects the RelB-p52 and RelB-p100 complexes are unique in the NF-B family. The N-terminal domain of p100/p52 interacts with RelB but not RelA. The transcriptional activation domain of RelB, but not RelA, directly interacts with the processing region of p100. These unique protein-protein contacts explain why RelB prefers p52 as its dimeric partner for transcriptional activity and is retained in the cytoplasm as an inhibited complex by p100. This association-mediated stabilization of RelB implies a possible role for RelB in the processing of p100 into p52.

Received for publication, September 20, 2007 , and in revised form, March 4, 2008.

^* This work is supported by funding from the National Institutes of Health and the Universitywide AIDS Research Program (to G. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the Heme training grant for predoctoral research, by a predoctoral fellowship from the Universitywide AIDS Research Program, and by a Cell Growth and Regulation Training Grant.

² Supported by predoctoral Graduate Assistance in Areas of National Need (GAANN) and American Heart Association fellowships.

³ Supported by a postdoctoral fellowship from the United States Army Breast Cancer Foundation.

⁴ To whom correspondence should be addressed: Dept. of Chemistry & Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0375. Tel.: 858-822-0470; E-mail: gghosh{at}ucsd.edu.

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