title: The p53 C terminus controls site-specific DNA binding and promotes structural changes within the central DNA binding domain.
abstract: DNA binding by numerous transcription factors including the p53 tumor suppressor protein constitutes a vital early step in transcriptional activation. While the role of the central core DNA binding domain (DBD) of p53 in site-specific DNA binding has been established, the contribution of the sequence-independent C-terminal domain (CTD) is still not well understood. We investigated the DNA-binding properties of a series of p53 CTD variants using a combination of in vitro biochemical analyses and in vivo binding experiments. Our results provide several unanticipated and interconnected findings. First, the CTD enables DNA binding in a sequence-dependent manner that is drastically altered by either its modification or deletion. Second, dependence on the CTD correlates with the extent to which the p53 binding site deviates from the canonical consensus sequence. Third, the CTD enables stable formation of p53-DNA complexes to divergent binding sites via DNA-induced conformational changes within the DBD itself.
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors: Oleg
authors: O
authors: Laptenko
authors: Department of Microbiology and Molecular Genetics, Hebrew University Medical School, IMRIC, Jerusalem 91120, Israel.
authors: Idit
authors: I
authors: Shiff
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors: Will
authors: W
authors: Freed-Pastor
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors: Andrew
authors: A
authors: Zupnick
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors: Melissa
authors: M
authors: Mattia
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors: Ella
authors: E
authors: Freulich
authors: Department of Microbiology and Molecular Genetics, Hebrew University Medical School, IMRIC, Jerusalem 91120, Israel.
authors: Inbal
authors: I
authors: Shamir
authors: Department of Microbiology and Molecular Genetics, Hebrew University Medical School, IMRIC, Jerusalem 91120, Israel.
authors: Noam
authors: N
authors: Kadouri
authors: Department of Microbiology and Molecular Genetics, Hebrew University Medical School, IMRIC, Jerusalem 91120, Israel.
authors: Tamar
authors: T
authors: Kahan
authors: Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors: James
authors: J
authors: Manfredi
authors: Department of Microbiology and Molecular Genetics, Hebrew University Medical School, IMRIC, Jerusalem 91120, Israel. Electronic address: itamarsi@ekmd.huji.ac.il.
authors: Itamar
authors: I
authors: Simon
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: clp3@columbia.edu.
authors: Carol
authors: C
authors: Prives
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D017434:Protein Structure, Tertiary; D020218:Response Elements; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA