The HCoV-HKU1 N-Terminal Domain Binds a Wide Range of 9-O-Acetylated Sialic Acids Presented on Different Glycan Cores

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(11), P. 3880 - 3890

Published: Oct. 12, 2024

Coronaviruses (CoVs) recognize a wide array of protein and glycan receptors by using the S1 subunit spike (S) glycoprotein. The contains two functional domains: N-terminal domain (S1-NTD) C-terminal (S1-CTD). S1-NTD SARS-CoV-2, MERS-CoV, HCoV-HKU1 possesses an evolutionarily conserved binding cleft that facilitates weak interactions with sialic acids on cell surfaces. employs 9-O-acetylated α2-8-linked disialylated structures for initial binding, followed TMPRSS2 receptor virus–cell fusion. Here, we demonstrate NTD has broader repertoire than previously recognized. We presented Fc chimeras nanoparticle system to mimic densely decorated surface HCoV-HKU1. These proteins were expressed HEK293S GnTI– cells, generating species carrying Man-5 structures, often observed near site CoVs. This multivalent presentation high mannose-containing revealed much profile compared its fully glycosylated counterpart. Using microarrays, α2-3-linked sialylated LacNAc are also bound, comparable OC43 NTD, suggesting glycan-binding modality. Further characterization specificity indicated promiscuous toward sialoglycans, independent core (glycolipids, N- or O-glycans). may employ additional sialoglycan trigger conformational changes in glycoprotein expose S1-CTD proteinaceous binding.

Language: Английский

#GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 5, 2023

Abstract Glycosylation of the SARS-CoV-2 spike (S) protein represents a key target for viral evolution because it affects both evasion and fitness. Successful variations in glycan shield are difficult to achieve though, as glycosylation is also critical folding structural stability. Within this framework, identification sites that structurally dispensable can provide insight into evolutionary mechanisms inform immune surveillance. In work we show through over 45 μs cumulative sampling from conventional enhanced molecular dynamics (MD) simulations, how structure immunodominant S receptor binding domain (RBD) regulated by N -glycosylation at N343 glycan’s role changes WHu-1, alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) omicron (BA.1 BA.2.86) variants. More specifically, find amphipathic nature -glycan instrumental preserve integrity RBD hydrophobic core loss triggers specific consistent conformational change. We change allosterically regulates conformation motif (RBM) RBDs, but not variants, due mutations reinforce architecture. support these findings, monosialylated ganglioside co-receptors highly dependent on RBD, affinity significantly across VoCs. Ultimately, functional reinforces our understanding function allows us identify constraints within which site become hotspot shield.

Language: Английский