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Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor.
Cell Host Microbe. 2020 10 07; 28(4):586-601.e6.CH

Abstract

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.

Links

Publisher Full Text
ncbi.nlm.nih.gov
linkinghub.elsevier.com
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Authors+Show Affiliations

Zhao P
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Praissman JL
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Grant OC
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Cai Y
Division of Molecular Medicine, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Xiao T
Division of Molecular Medicine, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Rosenbalm KE
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Aoki K
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Kellman BP
Departments of Pediatrics and Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
Bridger R
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Barouch DH
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Brindley MA
Department of Infectious Diseases, Department of Population Health, Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
Lewis NE
Departments of Pediatrics and Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Novo Nordisk Foundation Center for Biosustainability at UC San Diego, La Jolla, CA 92093, USA.
Tiemeyer M
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA.
Chen B
Division of Molecular Medicine, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Woods RJ
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA. Electronic address: rwoods@ccrc.uga.edu.
Wells L
Complex Carbohydrate Research Center, Department of Biochemistry and Molecular Biology, and Department of Chemistry, University of Georgia, Athens, GA 30602, USA. Electronic address: lwells@ccrc.uga.edu.

MeSH

Angiotensin-Converting Enzyme 2BetacoronavirusCOVID-19Coronavirus InfectionsGlycosylationHEK293 CellsHumansMolecular Dynamics SimulationPandemicsPeptidyl-Dipeptidase APneumonia, ViralProtein DomainsProtein Interaction Domains and MotifsReceptors, VirusSARS-CoV-2Spike Glycoprotein, CoronavirusVirus Internalization

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32841605

Citation

Zhao, Peng, et al. "Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor." Cell Host & Microbe, vol. 28, no. 4, 2020, pp. 586-601.e6.
Zhao P, Praissman JL, Grant OC, et al. Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor. Cell Host Microbe. 2020;28(4):586-601.e6.
Zhao, P., Praissman, J. L., Grant, O. C., Cai, Y., Xiao, T., Rosenbalm, K. E., Aoki, K., Kellman, B. P., Bridger, R., Barouch, D. H., Brindley, M. A., Lewis, N. E., Tiemeyer, M., Chen, B., Woods, R. J., & Wells, L. (2020). Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor. Cell Host & Microbe, 28(4), 586-e6. https://doi.org/10.1016/j.chom.2020.08.004
Zhao P, et al. Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor. Cell Host Microbe. 2020 10 7;28(4):586-601.e6. PubMed PMID: 32841605.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor. AU - Zhao,Peng, AU - Praissman,Jeremy L, AU - Grant,Oliver C, AU - Cai,Yongfei, AU - Xiao,Tianshu, AU - Rosenbalm,Katelyn E, AU - Aoki,Kazuhiro, AU - Kellman,Benjamin P, AU - Bridger,Robert, AU - Barouch,Dan H, AU - Brindley,Melinda A, AU - Lewis,Nathan E, AU - Tiemeyer,Michael, AU - Chen,Bing, AU - Woods,Robert J, AU - Wells,Lance, Y1 - 2020/08/24/ PY - 2020/06/26/received PY - 2020/07/22/revised PY - 2020/08/10/accepted PY - 2020/8/26/pubmed PY - 2020/10/27/medline PY - 2020/8/26/entrez KW - 3D modeling KW - ACE2 KW - COVID-19 KW - SARS-CoV-2 KW - Spike protein KW - coronavirus KW - glycoprotein KW - glycosylation KW - mass spectrometry KW - molecular dynamics SP - 586 EP - 601.e6 JF - Cell host & microbe JO - Cell Host Microbe VL - 28 IS - 4 N2 - 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. SN - 1934-6069 UR - https://www.unboundmedicine.com/medline/citation/32841605/Virus_Receptor_Interactions_of_Glycosylated_SARS_CoV_2_Spike_and_Human_ACE2_Receptor_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1931-3128(20)30457-1 DB - PRIME DP - Unbound Medicine ER -