Spike Protein and the Various Cell-Surface Carbohydrates: An Interaction Study

Abstract

The SARS-CoV-2 virus has been known to gain entry into the host cell through the spike protein that binds to the host ACE2 cell surface protein. However, the role of the putative sugar-binding sites in the spike protein has remained unclear. We provide a comprehensive in silico outlook into the infection initiation wherein the virus first recognizes the sialosides on the cell via its S1A domain of the spike protein as it surfs over the cell surface. This facilitates the subsequent interaction with the cellular glycosaminoglycans through the S1B domain of the spike protein as it binds to the ACE2 receptor. The unique coadaptation to recognize both the host protein and the cell-surface carbohydrate receptors provides an additional coupling mechanism for efficient viral attachment and infection.

Molecular interactions between perlecan LG3 and the SARS‐CoV‐2 spike protein receptor binding domain

“…Understanding the mechanisms by which SARS‐CoV‐2 obtains entry into host cells and the factors involved in viral infectivity is paramount to understanding viral pathogenesis and our ability to generate effective therapeutic interventions. While it is known that SARS‐CoV‐2 enters host cells via binding ACE2 (Hoffmann et al, 2020; Lan et al, 2020; Letko et al, 2020; Tian et al, 2020; Walls et al, 2020), other cell surfaces and nearby biomolecules such as ECM proteins have also shown a binding affinity for the SARS‐CoV‐2 spike protein RBD, although the extent to which these molecules modulate infectivity is still unclear (De Pasquale et al, 2021; Huang et al, 2022; Jayaprakash & Surolia, 2021; Lo et al., 2022; Mehdipour & Hummer, 2021; Nguyen et al, 2021; Yu et al, 2020). As recent studies have suggested that negatively charged heparan sulfate proteoglycans may act as a cofactor for SARS‐CoV‐2 binding to ACE2 known to have significant effects on vascular function and vascular barriers (Biering et al, 2022; Hashimoto et al, 2022; Martínez‐Salazar et al, 2022), we sought to characterize this interaction with the c‐terminal LG3 subdomain of perlecan domain V. To date, no conclusive studies have been conducted investigating the potential role that perlecan LG3 may have in SARS‐CoV‐2 pathogenesis.…”

Carbohydrate Ligands for COVID-19 Spike Proteins

“…Li et al showed that the N-terminal domain of β-coronaviridae spike protein S1 subunits (including SARS-CoV2) may potentially interact with unknown glycans [47]. Jayaprakash et al also indicated that the N-terminal domain of SARS-CoV-2 spike protein binds with sialosides by molecular modeling [35].…”

“…Clausen et al indicated that the SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and ACE2 through its receptor-binding domain [34]. Jayaprakash et al also showed that the S1A domain of the SARS-CoV-2 spike protein may interact with sialosides by molecular modeling [35]. Furthermore, the N-glycans of DC-SIGN and L-SIGN that were identified to be the receptors for SARS-CoV-2 could influence the entry of coronavirus [36].…”