Relationship between the evolution of sequence, structure and function in the intrinsically disordered Mastadenovirus E1A oncoprotein

LEONETTI CESAR OSVALDO; JULIANA GLAVINA; LUCIA CHEMES; IGNACIO ENRIQUE SANCHEZ

Mendoza

Conferencia; 10mo Congreso Argentino de Bioinformática y Biologı́a Computacional. 11 a 13 de Noviembre. Mendoza, Mendoza, Argentina; 2019

Asociacion Argentina de Bioinformática y Biología Computacional

BACKGROUND Viruses manipulate the host cell cycle by hijacking the host cell machinery. Many of these protein-protein interactions are mediated by short sequence elements named linear motifs (LMs) that are present in intrinsically disordered regions (IDRs). IDRs are thought to evolve rapidly compared to globular regions because of the lack of structural constraints. However, the evolutionary features of IDRs are poorly understood. The Mastadenovirus E1A oncoprotein, has a main role in host cell cycle deregulation. E1A is mainly intrinsically disordered and is enriched in LMs, which makes E1A a suitable model to study the relationship between structural and functional divergence of IDRs along the evolution of Mastadenoviruses. RESULTS Using a data set of 116 extant and 115 ancestral E1A sequences we studied for each sequence structural parameters such as predicted hydrodynamic radius, disorder (IUPred), secondary structure (TANGO) and distribution of oppositely charged residues (Kappa) and functional parameters such as LMs and predicted binding regions (ANCHOR). Both sets of parameters show a similar distribution between the extant and ancestral sequence data sets. We use the RMSD as a unit of distance to compare structural and functional parameters and correlate them to E1A sequence divergence. The RMSD distribution of the structural parameters shows that extension and charge patterning are strikingly conserved in highly divergent sequences, while secondary structure and LMs present higher variability. Next, we studied the RMSD trajectory along Mastadenovirus phylogenetic tree. The structural parameters and the prediction of binding regions using ANCHOR show a small variation, only between 6% and 15% of the extant sequences fall outside the main group. CONCLUSIONS The systematic study of functional and structural parameters of a prototypical IDR shows a range of behaviours where some structural features are highly conserved while other structural and functional features show less conservation along Mastadenovirus evolutionary history. These results suggest that IDRs are under a positive selection pressure to provide the right structural context for exposure of binding sites. This study paves the way to further understand the evolutionary features of IDRs and to expand the knowledge about E1A which is important for human health and the biotechnological field.disordered regions (IDRs). IDRs are thought to evolve rapidly compared to globular regions because of the lack of structural constraints. However, the evolutionary features of IDRs are poorly understood. The Mastadenovirus E1A oncoprotein, has a main role in host cell cycle deregulation. E1A is mainly intrinsically disordered and is enriched in LMs, which makes E1A a suitable model to study the relationship between structural and functional divergence of IDRs along the evolution of Mastadenoviruses. RESULTS Using a data set of 116