title: Sliding of p53 along DNA can be modulated by its oligomeric state and by cross-talks between its constituent domains.
abstract: The p53 protein is a homotetrameric transcription factor whose monomers comprise several domains. Although its organization with and without DNA was elucidated recently, characterizing the p53-DNA complex at the atomic level remains challenging because of its many disordered regions. Here we use computational models to predict the wiring of the four chains composing p53 and study its sliding dynamics along DNA in different oligomeric states. We find that helical sliding along the major groove is the most feasible DNA search mechanism for a large range of salt concentrations. Tighter packing of the tetrameric core domain is associated with a greater nonspecific affinity for DNA and the slowest linear diffusion dynamics along DNA. C-tails facilitate linear diffusion but restrict the association of two primary dimers into a tetramer. This restriction can disappear at higher salt concentrations, which decrease the affinity of C-tails for DNA, or upon interaction of the C-tail with other DNA segments. Our results support evidence for the positive regulation of p53 function by the C-tails and suggest that posttranslational charge modifications may alter the affinity of the tails for DNA. Conversely, the N-termini have little effect on sliding characteristics. Changes in the electrostatic potentials of the core domain via missense mutations corresponding to cancer development can also affect sliding by p53. Our study provides molecular insight into the role of various p53 domains during DNA search and indicates that the complex interdomain and protein-DNA cross-talks in which p53 engages may be related to its repertoire of cellular functions.
authors.affiliation: Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Netaly
authors.initials: N
authors.lastname: Khazanov
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Levy
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D012965:Sodium Chloride / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D012965:Sodium Chloride; D004247:DNA