19th-banner-rev.gif

Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

Deducing the multiple binding modes of p53 tetramer ? DNA interaction based on full-site palindrome of p53 response elements: convergence of sequence and geometry based recognitions

The p53 tetramer recognizes specifically a twenty base-pair DNA element. Here, we first examined symmetries encoded in p53 response elements (p53REs). We analyzed base inversion correlations within the half-site, as well as in the full-site palindrome. We found that p53REs are not only repeats of half-sites; rather, two p53 half-sites couple to form higher order 20 bps palindrome. The palindrome couplings between the half-sites are stronger for the human than for the mouse genome. The insertions between the two half-sites affect the level of couplings. The most notable feature is that the coupling between quarter-sites one and four dominates the p53REs without insertion. Insertion of three base pairs enhances the half-site palindrome. The statistical frequencies of the coupling between the half sites in the human genome correlate with grouped experimental p53 affinities with p53REs. The p53 tetramer may bind p53RE targets with different spacer lengths, and four-way Holliday junctions, suggesting different geometries and sequences. We propose that the palindromic sequence couplings may encode such potential preferred multiple binding modes of the p53 tetramer to DNA. We use DNA sequence analysis and perform molecular simulations. To construct the models we make use of the available dimer- and trimer-DNA crystal structures of the core domain which allow us to computationally test different modes. We test four binding modes for five native p53REs (p21-5?, GADD45, pDINP1, p53AIP1, and PUMA-BS2) and model the p53 in complex with the Holliday junction. We observe that alternative multiple binding modes are potentially feasible and may converge for different geometries. Four p53 monomers may potentially bind linear DNA with one mode in C2 symmetry. In an alternative arrangement with D2-like symmetry, p53 tetramer can conceivably recognize supercoiled DNA sequence-specifically and Holliday junction geometry-specifically.

Buyong Ma* 1, and
Arnold J. Levine 2

1BRP, SAIC-Frederick, Inc. Center for Cancer Research Nanobiology Program. NCI-Frederick, Frederick, MD 21702
2Institute for Advanced Study, Einstein Drive, Princeton, NJ 08540

Phone: 301-846-6540
Email: mab@ncifcrf.gov