Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion

Cell. 2019 Feb 21;176(5):1026-1039.e15. doi: 10.1016/j.cell.2018.12.028. Epub 2019 Jan 31.

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.

Keywords: MERS-CoV; N-linked glycosylation; SARS-CoV; class I fusion protein; coronavirus; glycoproteomics; membrane fusion; neutralizing antibodies; spike glycoprotein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • Chlorocebus aethiops
  • Coronavirus / immunology*
  • Coronavirus / metabolism
  • Coronavirus Infections / immunology
  • HEK293 Cells
  • Humans
  • Immunity, Humoral / immunology
  • Middle East Respiratory Syndrome Coronavirus / immunology
  • Middle East Respiratory Syndrome Coronavirus / metabolism
  • Molecular Mimicry / immunology
  • Protein Binding
  • Receptors, Virus / metabolism
  • SARS Virus / immunology
  • SARS Virus / metabolism
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Spike Glycoprotein, Coronavirus / physiology
  • Spike Glycoprotein, Coronavirus / ultrastructure*
  • Vero Cells
  • Virus Internalization

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus