Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion

Alexandra C Walls, M Alejandra Tortorici, Joost Snijder, Xiaoli Xiong, Berend-Jan Bosch, Felix A Rey, David Veesler

    Research output: Contribution to journalArticleAcademicpeer-review

    Abstract

    The tremendous pandemic potential of coronaviruses was demonstrated twice in the past few decades by two global outbreaks of deadly pneumonia. The coronavirus spike (S) glycoprotein initiates infection by promoting fusion of the viral and cellular membranes through conformational changes that remain largely uncharacterized. Here we report the cryoEM structure of a coronavirus S glycoprotein in the postfusion state, showing large-scale secondary, tertiary, and quaternary rearrangements compared with the prefusion trimer and rationalizing the free-energy landscape of this conformational machine. We also biochemically characterized the molecular events associated with refolding of the metastable prefusion S glycoprotein to the postfusion conformation using limited proteolysis, mass spectrometry, and single-particle EM. The observed similarity between postfusion coronavirus S and paramyxovirus F structures demonstrates that a conserved refolding trajectory mediates entry of these viruses and supports the evolutionary relatedness of their fusion subunits. Finally, our data provide a structural framework for understanding the mode of neutralization of antibodies targeting the fusion machinery and for engineering next-generation subunit vaccines or inhibitors against this medically important virus family.

    Original languageEnglish
    Pages (from-to)11157-11162
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume114
    Issue number42
    DOIs
    Publication statusPublished - 2017

    Keywords

    • coronavirus
    • fusion proteins
    • proteolytic activation
    • cryoEM
    • membrane fusion

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