A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71

Abstract

Enterovirus 71 (EV71), a major agent of hand-foot-and-mouth disease in children, can cause severe central nervous system disease and mortality. At present no vaccine or antiviral therapy is available. We have determined high-resolution structures for the mature virus and natural empty particles. The structure of the mature virus is similar to that of other enteroviruses, whilst the empty particles are dramatically expanded, with notable fissures, resembling elusive enterovirus uncoating intermediates not previously characterized in atomic detail. Hydrophobic capsid pockets within the EV71 capsid are collapsed in this expanded particle, providing a detailed explanation of the mechanism for receptor-binding triggered virus uncoating. The results provide a paradigm for enterovirus uncoating, in which the VP1 GH loop acts as an adaptor-sensor for the attachment of cellular receptors, converting heterologous inputs to a generic uncoating mechanism, spotlighting novel points for therapeutic intervention.

Cryo-EM study of slow bee paralysis virus at low pH reveals iflavirus genome release mechanism

“…2C). It was previously speculated that the disordered N-terminal parts of major capsid proteins VP1-3 of picornaviruses, which carry positively charged residues, are in direct contact with the genome (20). However, the N termini of the capsid proteins are fully determined in the crystal structure of SBPV (10), whereas the details of the RNA structure are not even partially resolved (Fig.…”

“…Amphipathic sequences from the N termini of VP1 and myristoylated VP4 subunits interact with endosome membranes and enable the delivery of enterovirus genomes into the cell cytoplasm (25)(26)(27). It has been previously proposed that the enterovirus genome leaves the capsid via a pore located at a twofold icosahedral axis (19)(20)(21). The resulting empty capsids are conventionally referred to as B particles (19).…”

“…1073/pnas.1616562114/-/DCSupplemental. particle surface, and released VP4 subunits (19)(20)(21)(22)(23)(24). Amphipathic sequences from the N termini of VP1 and myristoylated VP4 subunits interact with endosome membranes and enable the delivery of enterovirus genomes into the cell cytoplasm (25)(26)(27).…”

The Diamond Light Source and the challenges ahead for structural biology: some informal remarks

“…So in situ screening at Diamond, which allows potential crystals to be examined in an X-ray beam directly in the drop in the crystallization tray, has the potential to speed up this process. In the most advanced implementation of this, it is possible to actually collect and combine data from crystals in situ [15] and this was used to determine the structure of an entire virus [16]. By combining data from many crystals and limiting the dose on any particular one, it is thus possible to overcome radiation sensitivity.…”

“…Perhaps more important than the total number of structures being solved are the number of truly challenging projects being undertaken there. In addition to the outstanding examples in the accompanying articles in this volume, there are many others, including large macromolecular complexes [21,22], membrane proteins [23][24][25][26] and virus structures [16,27].…”