Structures of foot and mouth disease virus pentamers: Insight into capsid dissociation and unexpected pentamer reassociation.

Nayab Malik,Sarah Gold,David I Stuart,Elizabeth E Fry,Tobias J Tuthill,Abhay Kotecha,Amin Asfor,Juha T Huiskonen,Jingshan Ren,Yizhi Jane Tao

doi:10.1371/journal.ppat.1006607

Nayab Malik, Sarah Gold + Show 8 more

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https://doi.org/10.1371/journal.ppat.1006607

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Journal: PLoS Pathogens	Publication Date: Sep 22, 2017
Citations: 21	License type: CC BY 4.0

Affiliation: University of Oxford, The Pirbright Institute

Abstract

Foot-and-mouth disease virus (FMDV) belongs to the Aphthovirus genus of the Picornaviridae, a family of small, icosahedral, non-enveloped, single-stranded RNA viruses. It is a highly infectious pathogen and is one of the biggest hindrances to the international trade of animals and animal products. FMDV capsids (which are unstable below pH6.5) release their genome into the host cell from an acidic compartment, such as that of an endosome, and in the process dissociate into pentamers. Whilst other members of the family (enteroviruses) have been visualized to form an expanded intermediate capsid with holes from which inner capsid proteins (VP4), N-termini (VP1) and RNA can be released, there has been no visualization of any such state for an aphthovirus, instead the capsid appears to simply dissociate into pentamers. Here we present the 8-Å resolution structure of isolated dissociated pentamers of FMDV, lacking VP4. We also found these pentamers to re-associate into a rigid, icosahedrally symmetric assembly, which enabled their structure to be solved at higher resolution (5.2 Å). In this assembly, the pentamers unexpectedly associate ‘inside out’, but still with their exposed hydrophobic edges buried. Stabilizing interactions occur between the HI loop of VP2 and its symmetry related partners at the icosahedral 3-fold axes, and between the BC and EF loops of VP3 with the VP2 βB-strand and the CD loop at the 2-fold axes. A relatively extensive but subtle structural rearrangement towards the periphery of the dissociated pentamer compared to that in the mature virus provides insight into the mechanism of dissociation of FMDV and the marked difference in antigenicity.

Highlights

The Picornaviridae are small, non-enveloped, single-stranded RNA viruses, comprising numerous genera including the Enterovirus genus, Aphthovirus genus (e.g. Foot-and-mouth disease virus (FMDV) and Equine rhinitis A virus—ERAV) and Cardiovirus genus
This is the first structure of dissociated pentamers for FMDV, and for any picornavirus
We present the first visualization of a picornavirus particle assembled from pentamers comprising VP1, 2 and 3

Summary

Introduction

The Picornaviridae are small, non-enveloped, single-stranded RNA viruses, comprising numerous genera including the Enterovirus genus (e.g. poliovirus, human rhinovirus, enterovirus 71), Aphthovirus genus (e.g. FMDV and Equine rhinitis A virus—ERAV) and Cardiovirus genus (e.g. mengovirus). A final maturation cleavage of VP0 occurs in the presence of RNA, to produce VP4 (the N-terminal 85 residues of VP0) and VP2. Empty picornavirus capsids produced recombinantly [8] or by guanidine hydrochloride treatment to inhibit RNA synthesis, generally possess VP0 since the maturation cleavage (thought to be triggered in the context of the RNA) has not occurred and are generally less stable than their mature counterparts [9,10]. VP4 and the N-terminus of VP1 are believed to be involved in membrane penetration and have been observed to exit from a disassembly intermediate and to be transiently exposed on the mature capsid [11,12,13,14]

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