Structural and Functional Insights into the Evolution of SARS-CoV-2 KP.3.1.1 Spike Protein

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

Summary The JN.1-sublineage KP.3.1.1 recently emerged as the globally prevalent SARS-CoV-2 variant, demonstrating increased infectivity and antibody escape. We investigated how mutations a deletion in spike protein (S) affect ACE2 binding Mass spectrometry revealed new glycan site at residue N30 altered glycoforms neighboring N61. Cryo-EM structures showed that rearrangement of adjacent residues did not significantly change overall structure, up-down ratio receptor-binding domains (RBDs), or binding. Furthermore, S structure with hACE2 further confirmed an epistatic effect between F456L Q493E on Our analysis shows variants after late 2023 are now incorporating reversions to found other sarbecoviruses, including glycan, Q493E, others. Overall, these results inform structural functional consequences mutations, current evolutionary trajectory, immune evasion.

Language: Английский

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The role ofN-glycosylation in spike antigenicity for the SARS-CoV-2 Gamma variant

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

Published: April 7, 2023

Abstract The emergence of SARS-CoV-2 variants alters the efficacy existing immunity towards viral spike protein, whether acquired from infection or vaccination. Mutations that impact N -glycosylation may be particularly important in influencing antigenicity, but their consequences are difficult to predict. Here, we compare glycosylation profiles and antigenicity recombinant ancestral Wu-1 Gamma strain, which has two additional sites due amino acid substitutions N-terminal domain (NTD). We found a mutation at residue 20 threonine asparagine within NTD caused loss NTD-specific antibody binding. Glycan site-occupancy analyses revealed resulted switching new sequon N20 native N17 site. Site-specific demonstrated distinct glycoform differences between Wu-1, Gamma, selected variant proteins, these did not affect Finally, evaluated specificity proteins against convalescent COVID-19 sera reduced cross-reactivity some mutants, compared Wuhan spike. Our results illustrate divergence on binding profiles.

Language: Английский

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The Effect of Select SARS-CoV-2 N-Linked Glycan and Variant of Concern Spike Protein Mutations on C-Type Lectin-Receptor-Mediated Infection

Viruses, Journal Year: 2023, Volume and Issue: 15(9), P. 1901 - 1901

Published: Sept. 9, 2023

The SARS-CoV-2 virion has shown remarkable resilience, capable of mutating to escape immune detection and re-establishing infectious capabilities despite new vaccine rollouts. Therefore, there is a critical need identify relatively immutable epitopes on the that are resistant future mutations virus may accumulate. While hACE2 been identified as receptor mediates susceptibility, it only modestly expressed in lung tissue. C-type lectin receptors like DC-SIGN can act attachment sites enhance infection cells with moderate or low expression. We developed an easy-to-implement assay system allows for testing trans-infection. Using our assay, we assessed how Spike S1-domain glycans spike proteins from different strains affected ability pseudotyped lentivirions undergo DC-SIGN-mediated Through experiments seven glycan point mutants, two cluster mutants four spike, found N17 N122 appear have significant roles maintaining COVID-19′s capabilities. further cannot retain infectivity upon loss multiple glycosylation sites, Omicron BA.2 pseudovirions increased bind other non-lectin surface cells. Taken together, work opens door development therapeutics target overlooked prevent lectin-receptor-mediated trans-infection

Language: Английский

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The role of N-glycosylation in spike antigenicity for the SARS-CoV-2 gamma variant

Glycobiology, Journal Year: 2023, Volume and Issue: 34(2)

Published: Dec. 1, 2023

The emergence of SARS-CoV-2 variants alters the efficacy existing immunity towards viral spike protein, whether acquired from infection or vaccination. Mutations that impact N-glycosylation may be particularly important in influencing antigenicity, but their consequences are difficult to predict. Here, we compare glycosylation profiles and antigenicity recombinant ancestral Wu-1 Gamma strain, which has two additional sites due amino acid substitutions N-terminal domain (NTD). We found a mutation at residue 20 threonine asparagine within NTD caused loss NTD-specific antibody COVA2-17 binding. Glycan site-occupancy analyses revealed resulted switching new sequon N20 native N17 site. Site-specific demonstrated distinct glycoform differences between Wu-1, Gamma, selected variant proteins, these did not affect Finally, evaluated specificity proteins against convalescent COVID-19 sera reduced cross-reactivity some mutants, compared Wuhan spike. Our results illustrate divergence on binding profiles.

Language: Английский

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The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 5, 2024

Abstract Although it is well established that the SARS-CoV-2 spike glycoprotein binds to host cell ACE2 receptor initiate infection, far less known about tissue tropism and susceptibility virus. Differential expression across different types of heparan sulfate (HS) proteoglycans, with variably sulfated glycosaminoglycans (GAGs), their synergistic interactions viral N-glycans may contribute susceptibility. Nevertheless, contribution remains unclear since HS evade experimental characterization. We, therefore, carried out microsecond-long all-atom molecular dynamics simulations, followed by random acceleration fully glycosylated spike:ACE2 complex without highly GAG chains bound. By considering model GAGs as surrogates for expressed in lung cells, we identified key novel entry mechanisms SARS-CoV-2. We find promotes structural energetic stabilization active conformation binding domain (RBD) reorientation toward N-terminal same subunit RBD. Spike exert effects, promoting better packing, strengthening protein:protein interaction, prolonging residence time complex. trigger rearrangement S2’ functional protease cleavage site through allosteric interdomain communication. These results thus show has a multifaceted role facilitating infection they provide mechanistic basis development derivatives anti-SARS-CoV-2 potential. Significance Statement A blocking understand why infects some more than others. Heparan proteoglycans are differentially on surface cells and, receptors, an route Here, used computer simulations investigate how glycosaminoglycans, lungs, impact interaction between virus ACE2. The indicate HS, together N-glycans, stabilizes triggers changes, including cleavage, contributing mechanism. This study lays understanding cell-specificity developing strategies inhibiting infection.

Language: Английский

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