title: Comprehensive comparison of the interaction of the E2 master regulator with its cognate target DNA sites in 73 human papillomavirus types by sequence statistics.
abstract: Mucosal human papillomaviruses (HPVs) are etiological agents of oral, anal and genital cancer. Properties of high- and low-risk HPV types cannot be reduced to discrete molecular traits. The E2 protein regulates viral replication and transcription through a finely tuned interaction with four sites at the upstream regulatory region of the genome. A computational study of the E2-DNA interaction in all 73 types within the alpha papillomavirus genus, including all known mucosal types, indicates that E2 proteins have similar DNA discrimination properties. Differences in E2-DNA interaction among HPV types lie mostly in the target DNA sequence, as opposed to the amino acid sequence of the conserved DNA-binding alpha helix of E2. Sequence logos of natural and in vitro selected sites show an asymmetric pattern of conservation arising from indirect readout, and reveal evolutionary pressure for a putative methylation site. Based on DNA sequences only, we could predict differences in binding energies with a standard deviation of 0.64 kcal/mol. These energies cluster into six discrete affinity hierarchies and uncovered a fifth E2-binding site in the genome of six HPV types. Finally, certain distances between sites, affinity hierarchies and their eventual changes upon methylation, are statistically associated with high-risk types.
authors: Fundación Instituto Leloir and IIBBA-Conicet, Patricias Argentinas 435 (1405), Buenos Aires, Argentina.
authors: Ignacio E
authors: IE
authors: Sánchez
authors: Mariano
authors: M
authors: Dellarole
authors: Kevin
authors: K
authors: Gaston
authors: Gonzalo
authors: G
authors: de Prat Gay
mesh_terms: D052685:Alphapapillomavirus / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology; D017124:Conserved Sequence; D018899:CpG Islands; D019175:DNA Methylation; D004279:DNA, Viral / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D003627:Data Interpretation, Statistical; D019143:Evolution, Molecular; D023281:Genomics; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000378:metabolism; D030361:Papillomavirus Infections / Q000453:epidemiology / Q000821:virology; D011485:Protein Binding; D050436:Regulatory Elements, Transcriptional; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004279:DNA, Viral; D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D014157:Transcription Factors; C069102:oncogene protein E2, Human papillomavirus type 18