A highly conserved amino acid in VP1 regulates maturation of enterovirus 71.

Yong-Xin Zhang,Yong-Dong Zhou,Shan Cen,Yu-Ming Huang,Xiao-Yu Li,Jin-Ming Zhou,Quan-Jie Li,Fei Guo,Carolyn B Coyne

doi:10.1371/journal.ppat.1006625

Abstract

Enterovirus 71 (EV71) is the major causative agent of hand, foot and mouth disease (HFMD) in children, causing severe clinical outcomes and even death. Here, we report an important role of the highly conserved alanine residue at position 107 in the capsid protein VP1 (VP1A107) in the efficient replication of EV71. Substitutional mutations of VP1A107 significantly diminish viral growth kinetics without significant effect on viral entry, expression of viral genes and viral production. The results of mechanistic studies reveal that VP1A107 regulates the efficient cleavage of the VP0 precursor during EV71 assembly, which is required, in the next round of infection, for the transformation of the mature virion (160S) into an intermediate or A-particle (135S), a key step of virus uncoating. Furthermore, the results of molecular dynamic simulations and hydrogen-bond networks analysis of VP1A107 suggest that flexibility of the VP1 BC loop or the region surrounding the VP1107 residue directly correlates with viral infectivity. It is possible that sufficient flexibility of the region surrounding the VP1107 residue favors VP0 conformational change that is required for the efficient cleavage of VP0 as well as subsequent viral uncoating and viral replication. Taken together, our data reveal the structural role of the highly conserved VP1A107 in regulating EV71 maturation. Characterization of this novel determinant of EV71 virulence would promote the study on pathogenesis of Enteroviruses.

Highlights

Enterovirus 71 (EV71) is a small, non-enveloped, positive-stranded RNA virus, a member of the human enterovirus species A in the Enterovirus genus, the Picornaviridae family [1]
We have discovered, for the first time, that the alanine residue at position 107 of the capsid protein VP1 (VP1A107), which is present in almost all EV71 strains, plays an important role in the replication of EV71, since mutation of VP1A107 significantly impairs viral growth
Detailed mechanistic studies reveal that VP1A107 determines the efficient cleavage of the VP0 precursor during EV71 assembly, and subsequent virion uncoating in the round of viral infection

Summary

Introduction

Enterovirus 71 (EV71) is a small, non-enveloped, positive-stranded RNA virus, a member of the human enterovirus species A in the Enterovirus genus, the Picornaviridae family [1] This virus is the major causative agent of hand, foot and mouth disease (HFMD), a febrile illness that commonly affects young children. VP0 cleavage, called maturation cleavage, is hypothesized to be an autocatalytic event that results from the interactions between the structural proteins and the RNA genome during viral RNA encapsidation. This process is essential for virion stability and infectivity [13, 14]

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