Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion

Alexandra C. Walls, Xiaoli Xiong, Young Jun Park, M. Alejandra Tortorici, Joost Snijder, Joel Quispe, Elisabetta Cameroni, Robin Gopal, Mian Dai, Antonio Lanzavecchia, Maria Zambon, Félix A. Rey, Davide Corti, David Veesler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

337 Citations (Scopus)

Abstract

Recent outbreaks of severe acute respiratory syndrome and Middle East respiratory syndrome, along with the threat of a future coronavirus-mediated pandemic, underscore the importance of finding ways to combat these viruses. The trimeric spike transmembrane glycoprotein S mediates entry into host cells and is the major target of neutralizing antibodies. To understand the humoral immune response elicited upon natural infections with coronaviruses, we structurally characterized the SARS-CoV and MERS-CoV S glycoproteins in complex with neutralizing antibodies isolated from human survivors. Although the two antibodies studied blocked attachment to the host cell receptor, only the anti-SARS-CoV S antibody triggered fusogenic conformational changes via receptor functional mimicry. These results provide a structural framework for understanding coronavirus neutralization by human antibodies and shed light on activation of coronavirus membrane fusion, which takes place through a receptor-driven ratcheting mechanism. Structural analysis of the SARS-CoV S and MERS-CoV S glycoproteins in complex with neutralizing antibodies from human survivors sheds light into the mechanisms of membrane fusion and neutralization

Original languageEnglish
Pages (from-to)1026-1039.e15
JournalCell
Volume176
Issue number5
DOIs
Publication statusPublished - 21 Feb 2019

Bibliographical note

Funding Information:
We are grateful to Thomas Hinds and Ning Zheng for assistance with the crystallization robot and BLI device; to Jerome Cattin-Ortolà, Irini Topalidou, and Michael Ailion for assistance with western blotting; and to Michelle Chen (Wyatt technology) for her help with the light scattering experiments. This study was supported by the National Institute of General Medical Sciences ( R01GM120553 , D.V.), the National Institute of Allergy and Infectious Diseases ( HHSN272201700059C , D.V.), a Pew Biomedical Scholars Award (D.V.), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (D.V.), the Netherlands Organisation for Scientific Research ( Rubicon 019.2015.2.310.006 , J.S.), the European Molecular Biology Organization ( ALTF933-2015 , J.S.), the Zoonoses Anticipation and Preparedness Initiative ( IMI115760 , F.A.R.), the Pasteur Institute (M.A.T. and F.A.R.), the Centre National de la Recherche Scientifique (F.A.R.), the LabEx Integrative Biology of Emerging Infectious Diseases (F.A.R.), the University of Washington Arnold and Mabel Beckman CryoEM Center and Proteomics Resource ( UWPR95794 ), and the beamline 5.0.1 at the Advanced Light Source at Lawrence Berkley National Laboratory .

Funding Information:
We are grateful to Thomas Hinds and Ning Zheng for assistance with the crystallization robot and BLI device; to Jerome Cattin-Ortolà, Irini Topalidou, and Michael Ailion for assistance with western blotting; and to Michelle Chen (Wyatt technology) for her help with the light scattering experiments. This study was supported by the National Institute of General Medical Sciences (R01GM120553, D.V.), the National Institute of Allergy and Infectious Diseases (HHSN272201700059C, D.V.), a Pew Biomedical Scholars Award (D.V.), an Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund (D.V.), the Netherlands Organisation for Scientific Research (Rubicon 019.2015.2.310.006, J.S.), the European Molecular Biology Organization (ALTF933-2015, J.S.), the Zoonoses Anticipation and Preparedness Initiative (IMI115760, F.A.R.), the Pasteur Institute (M.A.T. and F.A.R.), the Centre National de la Recherche Scientifique (F.A.R.), the LabEx Integrative Biology of Emerging Infectious Diseases (F.A.R.), the University of Washington Arnold and Mabel Beckman CryoEM Center and Proteomics Resource (UWPR95794), and the beamline 5.0.1 at the Advanced Light Source at Lawrence Berkley National Laboratory.

Publisher Copyright:
© 2018 Elsevier Inc.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • MERS-CoV
  • N-linked glycosylation
  • SARS-CoV
  • class I fusion protein
  • coronavirus
  • glycoproteomics
  • membrane fusion
  • neutralizing antibodies
  • spike glycoprotein

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