Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor

• Published in: Cell host & microbe Vol. 28; no. 4; pp. 586 - 601.e6
• Main Authors: Zhao, Peng, Praissman, Jeremy L., Grant, Oliver C., Cai, Yongfei, Xiao, Tianshu, Rosenbalm, Katelyn E., Aoki, Kazuhiro, Kellman, Benjamin P., Bridger, Robert, Barouch, Dan H., Brindley, Melinda A., Lewis, Nathan E., Tiemeyer, Michael, Chen, Bing, Woods, Robert J., Wells, Lance
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-10-2020
• Subjects: 3D modeling; ACE2; Angiotensin-Converting Enzyme 2; Betacoronavirus - metabolism; coronavirus; Coronavirus Infections - enzymology; Coronavirus Infections - virology; COVID-19; glycoprotein; Glycosylation; HEK293 Cells; Humans; mass spectrometry; molecular dynamics; Molecular Dynamics Simulation; Pandemics; Peptidyl-Dipeptidase A - chemistry; Peptidyl-Dipeptidase A - metabolism; Pneumonia, Viral - enzymology; Pneumonia, Viral - virology; Protein Domains; Protein Interaction Domains and Motifs; Receptors, Virus - chemistry; Receptors, Virus - metabolism; SARS-CoV-2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Virus Internalization; COVID-19; ACE2; 3D modeling; SARS-CoV-2; Spike protein; coronavirus; glycosylation; mass spectrometry; glycoprotein; molecular dynamics
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2020.08.004

The SARS-CoV-2 betacoronavirus uses its highly glycosylated trimeric Spike protein to bind to the cell surface receptor angiotensin converting enzyme 2 (ACE2) glycoprotein and facilitate host cell entry. We utilized glycomics-informed glycoproteomics to characterize site-specific microheterogeneity of glycosylation for a recombinant trimer Spike mimetic immunogen and for a soluble version of human ACE2. We combined this information with bioinformatics analyses of natural variants and with existing 3D structures of both glycoproteins to generate molecular dynamics simulations of each glycoprotein both alone and interacting with one another. Our results highlight roles for glycans in sterically masking polypeptide epitopes and directly modulating Spike-ACE2 interactions. Furthermore, our results illustrate the impact of viral evolution and divergence on Spike glycosylation, as well as the influence of natural variants on ACE2 receptor glycosylation. Taken together, these data can facilitate immunogen design to achieve antibody neutralization and inform therapeutic strategies to inhibit viral infection.
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•Site-specific N-linked microheterogeneity is defined at 22 sites of SARS-CoV-2 Spike•Six sites of N-linked microheterogeneity of human ACE2 receptor are described•Molecular dynamics simulations of Spike and ACE2 show essential roles for glycosylation•We uncover roles for variants in protein-glycan and glycan-glycan interactions
Combining glycomics-informed glycoproteomics and bioinformatic analyses of variants with molecular dynamics simulations, Zhao et al. detail a role for glycan-protein and glycan-glycan interactions in the SARS-CoV-2 viral Spike protein-ACE2 human receptor complex.