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J. Biol. Chem., Vol. 281, Issue 29, 20494-20502, July 21, 2006

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Structure of the p53 Core Domain Dimer Bound to DNA^*

William C. Ho, Mary X. Fitzgerald, and Ronen Marmorstein¹

From the The Wistar Institute and Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The p53 tumor suppressor protein binds to DNA as a dimer of dimers to regulate transcription of genes that mediate responses to cellular stress. We have prepared a cross-linked trapped p53 core domain dimer bound to decamer DNA and have determined its structure by x-ray crystallography to 2.3Å resolution. The p53 core domain subunits bind nearly symmetrically to opposite faces of the DNA in a head-to-head fashion with a loophelix motif making sequence-specific DNA contacts and bending the DNA by about 20° at the site of protein dimerization. Protein subunit interactions occur over the central DNA minor groove and involve residues from a zinc-binding region. Analysis of tumor derived p53 mutations reveals that the dimerization interface represents a third hot spot for mutation that also includes residues associated with DNA contact and protein stability. Residues associated with p53 dimer formation on DNA are poorly conserved in the p63 and p73 paralogs, possibly contributing to their functional differences. We have used the dimeric protein-DNA complex to model a dimer of p53 dimers bound to icosamer DNA that is consistent with solution bending data and suggests that p53 core domain dimer-dimer contacts are less frequently mutated in human cancer than intra-dimer contacts.

Received for publication, April 14, 2006 , and in revised form, May 9, 2006.

The atomic coordinates and structure factors (code 2GEQ) 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 by National Institutes of Health Grant GM52880 and Department of Defense Grant W81XWH-04-1-0564 (both to R. M.), Department of Defense Grant DAMD17-02-1-0629 (to W. C. H.), and by a grant from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health (awarded to the Wistar Institute). 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 Fig. 1.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: The Wistar Inst., 3601 Spruce St., Rm. 327, Philadelphia, PA 19104. Tel.: 215-898-5006; Fax: 215-898-0381; E-mail: marmor{at}wistar.org.

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