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

• Published in: PLoS pathogens 2017-09, Vol.13 (9), p.e1006625-e1006625
• Main Authors: Zhang, Yong-Xin, Huang, Yu-Ming, Li, Quan-Jie, Li, Xiao-Yu, Zhou, Yong-Dong, Guo, Fei, Zhou, Jin-Ming, Cen, Shan
• Format: Article
• Language: English
• Subjects: Alanine; Amino acids; Amino Acids - genetics; Animals; Biology and Life Sciences; Biotechnology; Capsid protein; Capsid Proteins - metabolism; Care and treatment; Cercopithecus aethiops; Chemical properties; Children; Cleavage; Coxsackievirus infections; Enterovirus; Enterovirus A, Human - physiology; Enterovirus Infections - virology; Enteroviruses; Flexibility; Funding; Gene expression; Genetic transformation; Growth kinetics; Hand-foot-and-mouth disease; Infections; Infectivity; Kinetics; Maturation; Medical schools; Medicine and Health Sciences; Mutation; Mutation, Missense - genetics; Pathogenesis; Pathogens; Protein structure; Proteins; Replication; Research and Analysis Methods; Software; Transformation; Uncoating; Vero Cells - virology; Viral infections; Virions; Virology; Virulence; Virus Internalization; Virus Replication - genetics; Viruses; VP1 protein
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006625

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.