Structures of Coxsackievirus A10 unveil the molecular mechanisms of receptor binding and viral uncoating

Ling Zhu,Qiang Gao,Bin Zhu,Zihe Rao,Xiangxi Wang,Lei Cao,Yanjun Zhang,Yao Sun,Jinyan Fan,Hongrong Liu

doi:10.1038/s41467-018-07531-0

Abstract

Coxsackievirus A10 (CVA10), a human type-A Enterovirus (HEV-A), can cause diseases ranging from hand-foot-and-mouth disease to polio-myelitis-like disease. CVA10, together with some other HEV-As, utilizing the molecule KREMEN1 as an entry receptor, constitutes a KREMEN1-dependent subgroup within HEV-As. Currently, there is no vaccine or antiviral therapy available for treating diseases caused by CVA10. The atomic-resolution structure of the CVA10 virion, which is within the KREMEN1-dependent subgroup, shows significant conformational differences in the putative receptor binding sites and serotype-specific epitopes, when compared to the SCARB2-dependent subgroup of HEV-A, such as EV71, highlighting specific differences between the sub-groups. We also report two expanded structures of CVA10, an empty particle and uncoating intermediate at atomic resolution, as well as a medium-resolution genome structure reconstructed using a symmetry-mismatch method. Structural comparisons coupled with previous results, reveal an ordered signal transmission process for enterovirus uncoating, converting exo-genetic receptor-attachment inputs into a generic RNA release mechanism.

Highlights

Coxsackievirus A10 (CVA10), a human type-A Enterovirus (HEV-A), can cause diseases ranging from hand-foot-and-mouth disease to polio-myelitis-like disease
Coxsackievirus A10 (CVA10), belonging to the human type-A Enterovirus (HEV-A) subgroup, used to be associated mainly with herpangina, but in recent years has been increasingly reported to co-circulate with other members of the genus such as enterovirus 71 (EV71), CVA16 and CVA6 causing hand, foot, and mouth disease (HFMD) outbreaks in Asia, Europe, and North America[2,3]
A total of 4586, 22,725, and 21,456 particles were used to reconstruct the structures of CVA10 mature virus, empty- and A-particles with icosahedral symmetry imposed by single-particle techniques using Relion[19]

Summary

Introduction

Coxsackievirus A10 (CVA10), a human type-A Enterovirus (HEV-A), can cause diseases ranging from hand-foot-and-mouth disease to polio-myelitis-like disease. The mature virus releases the fatty acid molecule, leading to a cascade of structural changes, including the loss of VP1 N-terminus and VP4, resulting in the formation of an expanded particle, namely, A-particle or uncoating intermediate[9,10]. This is followed by delivery of the viral genome to the cytoplasm of the target cell via engagement with the endosomal membranes, leaving an empty particle or B-particle[11]. The structures of CVA10 reported in this study, which include lower resolution asymmetric information on the interaction of the genome with the A-particle, coupled with expanded particle structures from our previous investigations of EV71 and CVA16, allow us to propose a detailed molecular mechanism for the early stages of HEV uncoating

Methods

Results

Conclusion