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

  1. Gustavo Gámez
  2. Juan A. Hermoso
  3. César Carrasco-López
  4. Alejandro Gómez-Mejia
  5. Carlos E. Muskus
  6. Sven Hammerschmidt

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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.

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  1. ScreenIT

    SciScore for 10.1101/2021.04.09.439154: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    SGP or RBD structures considered for analysis were solved alone 68 or in complexed with their respective hACE2 receptor 28, or bound to antibodiesFab 153, nanobodies 13, sybodies 7 andor other ligandsinhibitorsbinders 7.
    antibodiesFab
    suggested: None
    Software and Algorithms
    SentencesResources
    By using the SnapGene software from GSL Biotech available at snapgene.com, we manually identified and curated all proteinencoding genes and other relevant traits on SARSCoV2 reference genome, according to the updated COVID19 scientific information publicly available in the literature.
    SnapGene
    suggested: (SnapGene, RRID:SCR_015052)
    Structure visualizations, manual inspection of NGlycan occupancy and other structural analyses, including residues interactions and structural alignments were performed using the PyMOL program the PyMOL Molecular Graphics System, Version 2.2.0,
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    To identify the SGP gene of each SARSCoV2 strain, we aligned the complete viral genomes to the SGP gene of SARSCoV2 reference sequence WuhanHu1, Accession number MN908947.3 or NC045512 by using MEGA version X53.
    MEGA
    suggested: (Mega BLAST, RRID:SCR_011920)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2021.04.09.439154v1 on bioRxiv