Interacting motif networks located in hotspots associated with RNA release are conserved in Enterovirus capsids

Abstract

Enteroviruses are responsible for a multitude of human diseases. Expansion of the virus capsid is associated with a cascade of conformational changes that allow the subsequent release of RNA. For the first time, this study presents a comprehensive bioinformatic screen for the prediction of interacting motifs within intraprotomer interfaces and across respective interfaces surrounding the fivefold and twofold axes. The results identify a network of conserved motif residues involved in interactions in enteroviruses that may be critical to capsid stabilisation, providing guidelines towards developing antivirals that interfere with viral expansion during RNA release.

The In Silico Prediction of Hotspot Residues that Contribute to the Structural Stability of Subunit Interfaces of a Picornavirus Capsid

“…The residues that critically contribute to the stability and assembly of picornavirus capsids remain poorly investigated. We previously identified a network of conserved interacting motifs within the subunit interfaces of enterovirus capsids and used in silico alanine scanning to elucidate hotspot residues within these preserved regions that contribute to the stability, assembly and uncoating of enteroviruses [36]. In the current study we made use of a different strategy for the prediction of hotspots in the TMEV capsid.…”

“…VP1 hotspots K241 and R249 were conserved in the cardioviruses, enteroviruses and FMDV. Residues K256 and R264 corresponding to K241 and R249 were previously found to be vital for EV-71 replication [20], while hotspots Y124, N204, F246 and R249 (VP1) are conserved with energetically important residues that were predicted to contribute to the stability of intraprotomer interfaces in the enteroviruses [36]. Several studies have recently speculated that interactions between VP4, the N-termini of VP1-3 and viral RNA also influence the dynamics of capsid stability [51,[58][59][60][61].…”

“…Most of the hotspots identified at the interpentamer interfaces in this study were conserved with residues in other picornaviruses that were previously predicted to stabilize the capsid. For example, hotspots N25, R61, Y62, Y63, T64, V95, R102, N117, S240 (VP2), M144, Y148, I150, D152, L153, T194 and T197 (VP3) correspond to residues in Seneca Valley virus 1 (SVV-1) that were proposed to form stabilizing interactions across the pentamer-pentamer interface [54], while hotspot residues R61, T64, (VP2), M144 and D152 (VP3) were conserved with residues that were predicted to be important for the stability of the pentamer interfaces of enteroviruses [36]. Furthermore, hotspots M144, I150, D152 and L153 (VP3) are conserved with residues in human rhinovirus (HRV)-2 that become disordered during uncoating and RNA release [56].…”

“…Few studies have attempted to theoretically investigate the residues critical to capsid assembly and stability in viruses within the Picornaviridae. 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]. The study contributed to the understanding of the conserved molecular determinants that modulate enterovirus capsid stability at a genus level; however, knowledge regarding the residues that critically contribute to the assembly and stability of capsids belonging to picornaviruses from other genera remains limited.…”

The generation and characterisation of neutralising antibodies against the Theiler’s murine encephalomyelitis virus (TMEV) GDVII capsid reveals the potential binding site of the host cell co-receptor, heparan sulfate

“…In cardiovirus capsids the 5-fold VP1 mesas are star shaped, whose points disrupt the canyon resulting instead in a series of hydrophobic pits (reviewed by Tuthill et al, 2010). Although the precise mechanism of picornavirus capsid assembly is poorly understood, mutational analyses of a small number of picornaviruses including FMDV and the enteroviruses, have identified residues in VP1-3 protein interfaces that are important for capsid function and structure (Ellard et al, 2017;Mateo et al, 2003;Rincón et al, 2015;Ross et al, 2017).…”