Identification of intrinsically disordered regions and linear motif mimicry across Flavivirus proteomes

PALOPOLI, NICOLÁS; GLAVINA JULIANA; CHEMES L.B.

Kosice

Conferencia; Conferencia NGP Net: "Action on Intrinsically Disordered Proteins".; 2017

NGP Net COST

Flaviviruses are a major threat for public health due to their high epidemic potential and the presence of multiple recent outbreaks in Latin America. Despite their clinical relevance, specific antiviral treatments are still lacking. Short Linear Motifs (SLiMs) mediating protein-protein interactions are appealing candidates as novel therapeutic targets, since these interactions rely on defined sequences and sufaces that could be targeted by specific inhibitory drugs. Viruses commonly manipulate the cell machinery by mimicking host SLiMs. However, while SLiMs are mostly present in intrinsically disordered regions (IDRs) of proteins, SLiMs and disordered regions in Flavivirus proteins are still poorly studied.Our goal was to define IDRs and identify putative SLiMs comprehensively across Flaviviridae groups including Dengue, Yellow Fever and Zika. We intend to infer the conservation of IDRs within and outside groups, identify SLiMs in these regions and assess their potential for binding cellular proteins by inspecting their sequence and structure properties.A comprehensive set of 128 sequences from Flaviviridae displayed intrinsic disorder ranging from 5-15% in different groups. Analysis of 13 proteins from 72 Flavivirus species and 361 corresponding structures revealed many conserved IDRs in several viral proteins including Capsid, NS3, NS2B and NS5, with small (5-30 residues) intrinsically disordered domains and structured, yet flexible regions within globular domains. While some IDRs were conserved across all groups, certain viral strains displayed unique disorder characteristics. A preliminary identification of SLiMs showed strongly conserved candidates, including those within the N-terminus of NS3, a region required for Dengue viral assembly and budding.Our analysis of Flavivirus proteomes reveals the presence of IDRs and several putative SLiMs that could be key for understanding poorly described aspects of these pathogens.