Etiology and Pathogenesis > Tumor Suppressor Genes

J. Biol. Chem., Vol. 281, Issue 29, 20494-20502, July 21, 2006; Originally published In Press as doi:10.1074/jbc.M603634200 on May 22, 2006

Abstract

Structure of the p53 Core Domain Dimer Bound to DNA

William C. Ho‡§, Mary X. Fitzgerald‡, and Ronen Marmorstein‡§1

From the ‡The Wistar Institute and §Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
1To 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@wistar.org.
Received for publication, April 14, 2006 , and in revised form, May 9, 2006.


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.

Copyright © 2006 by the American Society for Biochemistry and Molecular Biology.
Abstract | News


 
HOME | Detection | Diagnosis | Epidemiology | Etiology & Pathogenesis | Integrative Medicine | Overall Mngt & Case Reports | Prevention | Prognosis | Psychosocial Aspects | Treatment 
About BrainLife | Children's Corner | E-mail Alerts | Journals | Newsletter | Patients & Caregivers | Search | Stem Cells | WHO Classification | SITEMAP