To initiate infection, many viruses enter their host cells by triggering endocytosis following receptor engagement. However, the mechanisms by which non-enveloped viruses escape the endosome are poorly understood. Here we present near-atomic-resolution cryo-electron microscopy structures for feline calicivirus both undecorated and labelled with a soluble fragment of its cellular receptor, feline junctional adhesion molecule A. We show that VP2, a minor capsid protein encoded by all caliciviruses1,2, forms a large portal-like assembly at a unique three-fold axis of symmetry, following receptor engagement. This assembly—which was not detected in undecorated virions—is formed of twelve copies of VP2, arranged with their hydrophobic N termini pointing away from the virion surface. Local rearrangement at the portal site leads to the opening of a pore in the capsid shell. We hypothesize that the portal-like assembly functions as a channel for the delivery of the calicivirus genome, through the endosomal membrane, into the cytoplasm of a host cell, thereby initiating infection. VP2 was previously known to be critical for the production of infectious virus3; our findings provide insights into its structure and function that advance our understanding of the Caliciviridae.
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The icosahedral reconstruction of undecorated FCV and the C3-symmetrized reconstruction of FCV–fJAM-A are deposited in the Electron Microscopy Data Bank with accession numbers EMD-0054 and EMD-0056, respectively. The atomic coordinates for the FCV capsid asymmetric unit (VP1) are deposited in the RCSB Protein Data Bank with accession number 6GSH. The atomic coordinates for the FCV–fJAM-A portal vertex (VP1, VP2 and fJAM-A) are deposited in the RCSB Protein Data Bank with accession number 6GSI. Motion-corrected micrographs of undecorated and fJAM-A-labelled FCV (the raw data) are deposited in the EMPIAR Data Bank (https://www.ebi.ac.uk/pdbe/emdb/empiar/) with accession numbers EMPIAR-10192 and EMPIAR-10193, respectively.
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Cryo-electron microscopy data in this study were collected at the University of Leeds, Astbury BioStructure Laboratory. We thank S. Scheres for advice on the application of focused classification in Relion; R. Thompson for microscopy support; N. Ranson for microscope access and discussions; J. Hughes for advice on statistical analysis; and P. Stockley, M. Palmarini and J. McLauchlan for discussions. We acknowledge Diamond Light Source for time on Beamline B21 under Proposal MX11651-24. I.G.G. is a Wellcome Senior Fellow (Ref: 207498/Z/17/Z). M.J.C. was supported by a PhD studentship from the UK Biotechnology and Biological Sciences Research Council (BBSRC WestBIO DTP: BB/J013854/1). D.B. and M.M. are supported by the UK Medical Research Council (MC_UU_12014/7).
Nature thanks K. Y. Green and the other anonymous reviewer(s) for their contribution to the peer review of this work.