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 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.
Kitayner
Malka
M
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100.
Rozenberg
Haim
H
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100.
Kessler
Naama
N
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100.
Rabinovich
Dov
D
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100.
Shaulov
Lihi
L
Department of Biology, Technion, Technion City, Haifa 32000, Israel.
Haran
Tali E
TE
Department of Biology, Technion, Technion City, Haifa 32000, Israel. Electronic address: bitali@techunix.technion.ac.il.
Shakked
Zippora
Z
Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100. Electronic address: zippi.shakked@weizmann.ac.il.
D017209:Apoptosis; D001665:Binding Sites; D002453:Cell Cycle; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D004247:DNA