Structural Determinants within the Adenovirus Early Region 1A Protein Spacer Region Necessary for Tumorigenesis.
It has long been established that group A human adenoviruses (HAdV-A12, -A18, and -A31) can cause tumors in newborn rodents, with tumorigenicity related to the presence of a unique spacer region located between conserved regions 2 and 3 within the HAdV-A12 early region 1A (E1A) protein. Group B adenoviruses are weakly oncogenic, whereas most of the remaining human adenoviruses are nononcogenic. In an attempt to understand better the relationship between the structure of the AdE1A spacer region and oncogenicity of HAdVs, the structures of synthetic peptides identical or very similar to the adenovirus 12 E1A spacer region were determined and found to be α-helical using nuclear magnetic resonance (NMR) spectroscopy. This contrasts significantly with some previous suggestions that this region is unstructured. Using available predictive algorithms, the structures of spacer regions from other E1As were also examined, and the extent of the predicted α-helix was found to correlate reasonably well with the tumorigenicity of the respective virus. We suggest that this may represent an as-yet-unknown binding site for a partner protein required for tumorigenesis.IMPORTANCE This research analyzed small peptides equivalent to a region within the human adenovirus early region 1A protein that confers, in part, tumor-inducing properties to various degrees on several viral strains in rats and mice. The oncogenic spacer region is α-helical, which contrasts with previous suggestions that this region is unstructured. The helix is characterized by a stretch of amino acids rich in alanine residues that are organized into a hydrophobic, or "water-hating," surface that is considered to form a major site of interaction with cellular protein targets that mediate tumor formation. The extent of α-helix in E1A from other adenovirus species can be correlated to a limited degree to the tumorigenicity of that virus. Some serotypes show significant differences in predicted structural propensity, suggesting that the amino acid type and physicochemical properties are also of importance.
['Molloy|David P|DP|0000-0003-3880-607X', 'Grand|Roger J|RJ|']
D000260:Adenoviruses, Human D020816:Amino Acid Motifs D000818:Animals D063646:Carcinogenesis D021901:DNA, Intergenic D005057:Eukaryotic Cells D054884:Host-Pathogen Interactions D006801:Humans D051379:Mice D008958:Models, Molecular D009154:Mutation D019906:Nuclear Magnetic Resonance, Biomolecular D010455:Peptides D014176:Protein Biosynthesis D000072756:Protein Conformation, alpha-Helical D051381:Rats D065288:Serogroup D013329:Structure-Activity Relationship
nuclear magnetic resonance HAdV-A12 E1A oncogenesis structural motif