Abstract
The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler’s murine encephalomyelitis virus (TMEV) capsid. Significantly, many of the predicted hotspot residues were found to be conserved in representative viruses from different genera, suggesting that the molecular determinants of capsid assembly are conserved across the family. The analysis presented here can be applied to any icosahedral structure and provides a platform for in vitro mutagenesis studies to further investigate the significance of these hotspots in critical stages of the virus life cycle with a view to identify potential targets for antiviral drug design.
Highlights
The Picornaviridae are a heterogeneous family of small RNA viruses that includes etiological agents of significant human and animal diseases [1], such as foot-and-mouth disease virus (FMDV), poliovirus (PV), enterovirus 71 (EV-71) and hepatitis A virus (HAV) [2]
We previously developed an in silico approach employing computational alanine scanning to identify a network of hotspot residues in conserved motifs within the intraprotomer, interprotomer and interpentamer subunit interfaces of enterovirus capsids that are possibly involved in capsid uncoating and RNA release [36]
Our findings demonstrate that hotspot residues unique to Theiler’s murine encephalomyelitis virus (TMEV) are predominantly found at the intraand interprotomer interfaces of the capsid, but many hotspots in the same interfaces and those between pentamers are conserved in viruses from other genera, suggesting that molecular determinants of capsid stability may be somewhat conserved across the family
Summary
The Picornaviridae are a heterogeneous family of small RNA viruses that includes etiological agents of significant human and animal diseases [1], such as foot-and-mouth disease virus (FMDV), poliovirus (PV), enterovirus 71 (EV-71) and hepatitis A virus (HAV) [2]. The study contributed to the understanding of the conserved molecular determinants that modulate enterovirus capsid stability at a genus level; knowledge regarding the residues that critically contribute to the assembly and stability of capsids belonging to picornaviruses from other genera remains limited Identifying these specific residues in other picornaviruses is imperative for a comprehensive understanding of picornavirus capsids and how they are assembled and disassembled, and for the development of improved broad-spectrum strategies to control these significant viruses. The present study elucidates the residues at the intraprotomer, interprotomer and interpentamer interfaces that contribute to the stability and assembly of the Theiler’s murine encephalomyelitis virus (TMEV) capsid, using an in silico screen that combines five readily accessible energy- and feature-based models for hotspot prediction.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call