Structural order and disorder dictate sequence and functional evolution of the papillomavirus E7 protein

LUCÍA B. CHEMES; JULIANA GLAVINA; CRISTINA MARINO-BUSLJE; GONZALO DE PRAY-GAY; IGNACIO E. SÁNCHEZ

Córdoba - Provincia de Córdoba

Congreso; Segundo Congreso Argentino de Bioinformática y Biología Computacional; 2011

Asociación Argentina de Bioinformática y Biología Computacional

Papillomaviruses are a group of small, double-stranded DNA viruses that infect the skin and mucous epithelia of reptiles, birds and mammals. Over 200 types have been identified, including more than 100 of types that infect humans and 19 high-risk types that can cause cervical cancer. The E6 and E7 papillomavirus proteins are responsible for cellular transformation through interaction with key host protein targets, with E7 showing stronger transformation potential than E6. The E7 protein consists of an intrinsically disordered N-terminal domain (E7N) and a dimeric, globular C-terminal domain (E7C). E7N binds host protein targets through several short linear sequence motifs, such as the LxCxE motif and the CKII/PEST region. We study conservation and coevolution of E7N and E7C residues across papillomaviruses. E7N shows a high degree of conservation along its whole length, without any long stretches of low conservation. The conserved residues lying between the known motifs may connect the known motifs physically, allowing the functional coupling between distant sites. We observe a diversity of motif arrangements within E7N in the papillomavirus family: each of the known motifs is fully present in some genera, partially present in some others and altogether missing from certain genera. The changes in the E7N functional motifs do not follow the phylogenetic relationships between papillomavirus types, indicating that these changes have occurred independently several times in the recent past. Thus, structural disorder in E7N has facilitated adaptive evolution of short functional motifs. The globular E7C domain shows a conservation pattern that is by large explained by its main functions of zinc binding and dimerization. Additionally, four conserved residues on the surface of the domain have been proposed to form a binding surface targeting short linear sequence motifs from host proteins. We show that the proposed binding surface is conserved in evolutionarily related host proteins and examine the specificity of the interaction using the sequences of known targets. Altogether, our results show how structural order and disorder dictate the mutational landscape of the E7 protein and, with it, its functional evolution.