Evolution of linear motifs within the adenovirus E1A oncoprotein

JULIANA GLAVINA; LUCÍA B. CHEMES; ROCÍO ESPADA; RICARDO RODRÍGUEZ DE LA VEGA; IGNACIO E. SÁNCHEZ

San Carlos de Bariloche

Congreso; 5to. Congreso Argentino de Bioinform ́ atica y Biolog ́ıa Compu- tacional; 2014

Introduction. Many protein-protein interactions are mediated by linear sequence motifs of ~5 function-determining residues, which are often found within intrinsically disordered domains. Linear motifs appear or disappear with only a handful of point mutations and are thought to evolve rapidly. We have chosen the adenovirus E1A oncoprotein as a model to study sequence conservation and linear motif evolution. The E1A protein is unique to the adenovirus Genus Mastadenovirus, which infects mammals. Mastadenovirus types differ in their phenotypical traits, including host, tissue tropisms and oncogenic potential. E1A consists of 4 intrinsically disordered regions, designated Nt, CR1, CR2 and CR4, and one globular region designated CR3. We have analyzed the variability and evolution of 13 linear motifs in E1A and the relationship between different motif repertoires and virus phenotypes. Methods. We used over 100 E1A sequences from known mastadenovirus types to construct an alignment. We used the information content of each position in the alignment as a measure of conservation. Direct information is a measure used to infer direct co-evolutionary couplings among residue pairs in multiple sequence alignments, taking to a minimum the influence of indirect correlations. We used this approach to predict residue-residue contacts on the E1A protein. We also studied the variability in the linear motif repertoire for different E1A proteins. The motif repertoire was then represented superimposed on a phylogenetic tree of Mastadenoviruses. Last, we performed hypergeometric association tests on all individual combinations of linear motifs, phenotypic traits and hosts. Results. The E1A protein is densely packed with linear motifs that explain the high number of binding partners. The intrinsically disordered regions and the the globular CR3 region show a high degree of conservation along the whole length. We found pairs of co-evolving residues within each region as well as across regions. The different motifs showed different abundance and distribution patterns. Some were highly conserved and some were present only in a few species. Conclusions. E1A linear motifs evolve rapidly and follow motif-specific trends. The different motifs and regions of the protein did not evolve independently as shown by co-evolution, and evolutionary analyses. A lack of globular structure does not necessarily lead to a lower degree of sequence conservation.