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J. Biol. Chem., Vol. 283, Issue 30, 21179-21186, July 25, 2008

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Crystal Structure of the BARD1 Ankyrin Repeat Domain and Its Functional Consequences^*

David Fox, III, Isolde Le Trong, Ponni Rajagopal, Peter S. Brzovic, Ronald E. Stenkamp, and Rachel E. Klevit¹

From the Department of Biochemistry, University of Washington, Seattle, Washington 98195-7350 and the Department of Biological Structure and Biomolecular Structure Center, University of Washington, Seattle, Washington 98195

BARD1 is the constitutive nuclear partner to the breast and ovarian cancer-specific tumor suppressor BRCA1. Together, they form a heterodimeric complex responsible for maintaining genomic stability through nuclear functions involving DNA damage signaling and repair, transcriptional regulation, and cell cycle control. We report the 2.0Å structure of the BARD1 ankyrin repeat domain. The structure includes four ankyrin repeats with a non-canonical C-terminal capping ankyrin repeat and a well ordered extended loop preceding the first repeat. Conserved surface features show an acidic patch and an acidic pocket along the surface typically used by ankyrin repeat domains for binding cognate proteins. We also demonstrate that two reported mutations, N470S and V507M, in the ankyrin repeat domain do not result in observable structural defects. These results provide a structural basis for exploring the biological function of the ankyrin repeat domain and for modeling BARD1 isoforms.

Received for publication, March 25, 2008

The atomic coordinates and structure factors (code 3C5R) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported, in whole or in part, by National Institutes of Health Grants NIH 5 1RO1CA79963 and NIH MBTG T32GM008268-(17-19). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental figures, a supplemental table, and supplemental text.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, University of Washington, Box 357350, Seattle, Washington 98195-7350. E-mail: klevit{at}u.washington.edu.

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