Structural Basis of DNA Recognition by p53 Tetramers

The tumor-suppressor protein p53 is among the most effective of the cell's natural defenses against cancer. In response to cellular stress, p53 binds as a tetramer to diverse DNA targets containing two decameric half-sites, thereby activating the expression of genes involved in cell-cycle arres...

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Bibliographic Details
Published in:Molecular cell 2006-06, Vol.22 (6), p.741-753
Main Authors: Kitayner, Malka, Rozenberg, Haim, Kessler, Naama, Rabinovich, Dov, Shaulov, Lihi, Haran, Tali E., Shakked, Zippora
Format: Article
Language:English
Subjects:
Apoptosis
Binding Sites
Cell Cycle
CELLCYCLE
Crystallography, X-Ray
DNA
DNA - chemistry
DNA - metabolism
Gene Expression Regulation, Neoplastic
Models, Molecular
Neoplasms - metabolism
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
Structure-Activity Relationship
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - metabolism
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Summary:The tumor-suppressor protein p53 is among the most effective of the cell's natural defenses against cancer. In response to cellular stress, p53 binds as a tetramer to diverse DNA targets containing two decameric half-sites, thereby activating the expression of genes involved in cell-cycle arrest or apoptosis. Here we present high-resolution crystal structures of sequence-specific complexes between the core domain of human p53 and different DNA half-sites. In all structures, four p53 molecules self-assemble on two DNA half-sites to form a tetramer that is a dimer of dimers, stabilized by protein-protein and base-stacking interactions. The protein-DNA interface varies as a function of the specific base sequence in correlation with the measured binding affinities of the complexes. The new data establish a structural framework for understanding the mechanisms of specificity, affinity, and cooperativity of DNA binding by p53 and suggest a model for its regulation by regions outside the sequence-specific DNA binding domain.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2006.05.015