How p53 binds DNA as a tetramer

Kevin G. McLure, Patrick W.K. Lee

Research output: Contribution to journalArticlepeer-review

216 Citations (Scopus)

Abstract

The p53 tumor suppressor protein is a tetramer that binds sequence-specifically to a DNA consensus sequence consisting of two consecutive half-sites, with each half-site being formed by two head-to-head quarter-sites (→← →←). Each p53 subunit binds to one quarter-site, resulting in all four DNA quarter-sites being occupied by one p53 tetramer. The tetramerization domain forms a symmetric dimer of dimers, and two contrasting models have the two DNA-binding domains of each dimer bound to either consecutive or alternating quarter-sites. We show here that the two monomers within a dimer bind to a half-site (two consecutive quarter-sites), but not to separated (alternating) quarter-sites. Tetramers bind similarly, with the two dimers within each tetramer binding to pairs of half-sites. Although one dimer within the tetramer is sufficient for binding to one half-site in DNA, concurrent interaction of the second dimer with a second half-site in DNA drastically enhances binding affinity (at least 50-fold). This cooperative dimer-dimer interaction occurs independently of tetramerization and is a primary mechanism responsible for the stabilization of p53 DNA binding. Based on these findings, we present a model of p53 binding to the consensus sequence, with the tetramer binding DNA as a pair of clamps.

Original languageEnglish
Pages (from-to)3342-3350
Number of pages9
JournalEMBO Journal
Volume17
Issue number12
DOIs
Publication statusPublished - Jun 15 1998
Externally publishedYes

ASJC Scopus Subject Areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology

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McLure, K. G., & Lee, P. W. K. (1998). How p53 binds DNA as a tetramer. EMBO Journal, 17(12), 3342-3350. https://doi.org/10.1093/emboj/17.12.3342