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Atypical N-glycosylation of SARS-CoV-2 impairs the efficient binding of Spike-RBM to the human-host receptor hACE2

View ORCID ProfileGustavo Gámez, View ORCID ProfileJuan A. Hermoso, View ORCID ProfileCésar Carrasco-López, View ORCID ProfileAlejandro Gómez-Mejia, View ORCID ProfileCarlos E. Muskus, View ORCID ProfileSven Hammerschmidt
doi: https://doi.org/10.1101/2021.04.09.439154
Gustavo Gámez
1Genetics, Regeneration and Cancer (GRC) Research Group, University Research Center (SIU), University of Antioquia, UdeA, 050010 Medellín, Colombia
2Basic and Applied Microbiology (MICROBA) Research Group, School of Microbiology, University of Antioquia, UdeA, 050010 Medellín, Colombia
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  • For correspondence: gustavo.gamez@udea.edu.co
Juan A. Hermoso
3Department of Crystallography and Structural Biology, Institute of Physical Chemistry “Rocasolano”, CSIC, 28006 Madrid, Spain
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César Carrasco-López
4Department of Chemical and Biological Engineering, Princeton University, Princeton NJ 08544
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Alejandro Gómez-Mejia
5Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091, Zurich, Switzerland
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Carlos E. Muskus
6Program for the Study and Control of Tropical Diseases-PECET, Faculty of Medicine, University of Antioquia, 050010 Medellín, Colombia
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Sven Hammerschmidt
7Department of Molecular Genetics and Infection Biology, Interfaculty Institute for Genetics and Functional Genomics, Center for Functional Genomics of Microbes, University of Greifswald, 17487 Greifswald, Germany
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Abstract

SARS-CoV-2 internalization by human host cells relies on the molecular binding of its spike glycoprotein (SGP) to the angiotensin-converting-enzyme-2 (hACE2) receptor. It remains unknown whether atypical N-glycosylation of SGP modulates SARS-CoV-2 tropism for infections. Here, we address this question through an extensive bioinformatics analysis of publicly available structural and genetic data. We identified two atypical sequons (sequences of N-glycosylation: NGV 481-483 and NGV 501-503), strategically located on the receptor-binding motif (RBM) of SGP and facing the hACE2 receptor. Interestingly, the cryo-electron microscopy structure of trimeric SGP in complex with potent-neutralizing antibodies from convalescent patients revealed covalently-linked N-glycans in NGV 481-483 atypical sequons. Furthermore, NGV 501-503 atypical sequon involves the asparagine-501 residue, whose highly-transmissible mutation N501Y is present in circulating variants of major concerns and affects the SGP-hACE2 binding-interface through the well-known hotspot-353. These findings suggest that atypical SGP post-translational modifications modulate the SGP-hACE2 binding-affinity affecting consequently SARS-CoV-2 transmission and pathogenesis.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 10, 2021.
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Atypical N-glycosylation of SARS-CoV-2 impairs the efficient binding of Spike-RBM to the human-host receptor hACE2
Gustavo Gámez, Juan A. Hermoso, César Carrasco-López, Alejandro Gómez-Mejia, Carlos E. Muskus, Sven Hammerschmidt
bioRxiv 2021.04.09.439154; doi: https://doi.org/10.1101/2021.04.09.439154
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Atypical N-glycosylation of SARS-CoV-2 impairs the efficient binding of Spike-RBM to the human-host receptor hACE2
Gustavo Gámez, Juan A. Hermoso, César Carrasco-López, Alejandro Gómez-Mejia, Carlos E. Muskus, Sven Hammerschmidt
bioRxiv 2021.04.09.439154; doi: https://doi.org/10.1101/2021.04.09.439154

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