Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion

• Published in: Cell Vol. 176; no. 5; pp. 1026 - 1039.e15
• Main Authors: Walls, Alexandra C., Xiong, Xiaoli, Park, Young-Jun, Tortorici, M. Alejandra, Snijder, Joost, Quispe, Joel, Cameroni, Elisabetta, Gopal, Robin, Dai, Mian, Lanzavecchia, Antonio, Zambon, Maria, Rey, Félix A., Corti, Davide, Veesler, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.02.2019; Elsevier
• Subjects: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing; Antibodies, Neutralizing - immunology; Antibodies, Viral; Antibodies, Viral - immunology; Chlorocebus aethiops; class I fusion protein; Coronavirus; Coronavirus - immunology; Coronavirus - metabolism; Coronavirus Infections; Coronavirus Infections - immunology; glycoproteins; glycoproteomics; HEK293 Cells; Humans; humoral immunity; Immunity, Humoral; Immunity, Humoral - immunology; Life Sciences; membrane fusion; MERS-CoV; Middle East Respiratory Syndrome Coronavirus; Middle East Respiratory Syndrome Coronavirus - immunology; Middle East Respiratory Syndrome Coronavirus - metabolism; Molecular Mimicry; Molecular Mimicry - immunology; N-linked glycosylation; neutralization; neutralizing antibodies; pandemic; Protein Binding; Receptors, Virus; Receptors, Virus - metabolism; SARS Virus; SARS Virus - immunology; SARS Virus - metabolism; SARS-CoV; Severe acute respiratory syndrome coronavirus; spike glycoprotein; Spike Glycoprotein, Coronavirus; Spike Glycoprotein, Coronavirus - metabolism; Spike Glycoprotein, Coronavirus - physiology; Spike Glycoprotein, Coronavirus - ultrastructure; Vero Cells; Virus Internalization; viruses; glycoproteomics; spike glycoprotein; SARS-CoV; coronavirus; neutralizing antibodies; MERS-CoV; N-linked glycosylation; class I fusion protein; membrane fusion
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2018.12.028

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. [Display omitted] •MERS-CoV/SARS-CoV S composite glycan shields analyzed by cryo-EM and mass spectrometry•Structures of MERS-CoV/SARS-CoV S with neutralizing antibodies from survivors•LCA60 inhibits receptor binding by interacting with MERS-CoV S protein/glycans•S230 blocks receptor binding and triggers fusogenic rearrangements via functional mimicry 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