Structures of Echovirus 30 in complex with its receptors inform a rational prediction for enterovirus receptor usage

Kang Wang,Xiangxi Wang,Minhao Li,George F Gao,Xin Zhao,Ling Zhu,Lunbiao Cui,Zihe Rao,Fengcai Zhu,Yao Sun,Weiwei Zhai,Li Zhang

doi:10.1038/s41467-020-18251-9

Abstract

Receptor usage that determines cell tropism and drives viral classification closely correlates with the virus structure. Enterovirus B (EV-B) consists of several subgroups according to receptor usage, among which echovirus 30 (E30), a leading causative agent for human aseptic meningitis, utilizes FcRn as an uncoating receptor. However, receptors for many EVs remain unknown. Here we analyzed the atomic structures of E30 mature virion, empty- and A-particles, which reveals serotype-specific epitopes and striking conformational differences between the subgroups within EV-Bs. Of these, the VP1 BC loop markedly distinguishes E30 from other EV-Bs, indicative of a role as a structural marker for EV-B. By obtaining cryo-electron microscopy structures of E30 in complex with its receptor FcRn and CD55 and comparing its homologs, we deciphered the underlying molecular basis for receptor recognition. Together with experimentally derived viral receptor identifications, we developed a structure-based in silico algorithm to inform a rational prediction for EV receptor usage.

Highlights

Receptor usage that determines cell tropism and drives viral classification closely correlates with the virus structure
A number of receptors have been identified and known to facilitate the entry of EVs, including scavenger receptor B2 (SCARB2; a receptor for EV71, CVA16 and a subgroup of EV-A), Kringlecontaining trans-membrane protein (KREMEN1 for another subgroup of EV-A, including CVA10), coxsackie and adenovirus receptor (CAR; the uncoating receptor for one subgroup of Enterovirus B (EV-B), including all six serotypes of CVBs), CD55, the newly identified Neonatal Fc Receptor (FcRn; the uncoating receptor for another major subgroup of EV-B, containing echovirus 30 (E30)), Intercellular adhesion molecule 1 (ICAM1; the uncoating receptor for one subgroup of EV-C, including CVA21 and CVA24v) and CD155 known as PVR17,28–32
Most enteroviruses rely on an uncoating receptor to trigger the destabilizing rearrangements of capsid proteins, leading to the formation of a capsid mediated channel that connects the capsid two-fold pore and the endosomal membrane, through which the viral genome is released into the cytoplasm[8]

Summary

Introduction

Receptor usage that determines cell tropism and drives viral classification closely correlates with the virus structure. Enterovirus B (EV-B) consists of several subgroups according to receptor usage, among which echovirus 30 (E30), a leading causative agent for human aseptic meningitis, utilizes FcRn as an uncoating receptor. Capsid structures for many EVs have been studied extensively[6,7,8,9,10,11,12,13,14,15,16,17,18,19], large gaps in our knowledge concerning determinants of specificity between the serotypes/subgroups and characteristics for receptor usage in EV-Bs still exist. EV entry involves two key steps: (I) attachment, in which the virus binds to attachment receptors on the surface of the host cell; and (II) uncoating, in which the viral genome is released from viral particles into host cells[23]. Virus–receptor interactions have been well characterized for several EVs, there remain a large number of viruses, especially those in more recently identified genera, whose receptors are yet to be identified

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Conclusion