#GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern DOI Creative Commons
Callum M. Ives, Linh Nguyen, Carl A. Fogarty

et al.

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

Role of N343 glycosylation on the SARS-CoV-2 S RBD structure and co-receptor binding across variants of concern DOI Creative Commons
Callum M. Ives, Linh Nguyen, Carl A. Fogarty

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: June 12, 2024

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) alpha, 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 work reinforces our understanding function allows us identify constraints within which site become hotspot shield.

Language: Английский

Citations

1
Conserved role of spike S2 domain N-glycosylation across beta-coronavirus family DOI Creative Commons
Qi Yang, Anju Kelkar, Balaji Manicassamy

et al.

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

Published: Sept. 5, 2024

Abstract Besides acting as an immunological shield, the N-glycans of SARS-CoV-2 are also critical for viral life cycle. As S2 subunit spike is highly conserved across beta-coronaviruses, we determined functional significance five ‘stem N-glycans’ located in between N1098-N1194. Studies were performed with 31 Asn-to-Gln mutants, beta-coronavirus virus-like particles and single-cycle replicons. Deletions stem enhanced S1 shedding from trimeric spike, reduced ACE2 binding abolished syncytia formation. When three or more deleted, expression on cell surface incorporation into virions was both reduced. Viral entry function progressively lost upon deleting N1098 glycan combination additional glycosite modifications. In addition to SARS-CoV-2, SARS-CoV MERS-CoV prevented target cells. These data suggest multiple roles N-glycans, evolutionarily properties these complex carbohydrates human beta-coronaviruses. Author Summary Previous work shows that N-linked glycans essential Few natural mutations have been observed S2-subunit glycoprotein GISAID data, absent post-fusion structure lie equidistant, ~4 nm apart, suggesting significance. Upon testing hypothesis function, noted including regulation S1-subunit shedding, cells virions, syncytial formation/cell-cell fusion entry. other Thus, represent targets development countermeasures against future outbreaks.

Language: Английский

Citations

1
Distinct pathways for evolution of enhanced receptor binding and cell entry in SARS-like bat coronaviruses DOI Creative Commons
Alexandra L. Tse, Cory M. Acreman, Inna Ricardo-Lax

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(11), P. e1012704 - e1012704

Published: Nov. 15, 2024

Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent CoVs to investigate their cell entry mechanisms. Unexpectedly, successful recovery of rVSVs spike SHC014-CoV, a SARS-like CoV, was associated with acquisition novel substitution in S2 fusion peptide-proximal region (FPPR). This enhanced viral both VSV and coronavirus contexts increasing availability receptor-binding domain recognize its cellular receptor, ACE2. A second S1 N–terminal domain, uncovered through rescue serial passage virus FPPR substitution, further spike:ACE2 interaction entry. Our findings identify genetic pathways adaptation during spillover host-to-host transmission, fitness trade-offs inherent these pathways, potential Achilles’ heels that could be targeted countermeasures.

Language: Английский

Citations

1
Towards a molecular picture of the archaeal cell surface DOI Creative Commons
Matthew C. Gaines, Michail N. Isupov, Mathew McLaren

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 29, 2024

Language: Английский

Citations

1
Impact of glycosylation on viral vaccines DOI

Antonio Lembo,

Antonio Molinaro, Cristina De Castro

et al.

Carbohydrate Polymers, Journal Year: 2024, Volume and Issue: 342, P. 122402 - 122402

Published: June 16, 2024

Language: Английский

Citations

1
SARS-CoV-2 spike glycosylation affects function and neutralization sensitivity DOI Creative Commons

Fengwen Zhang,

Fabian Schmidt,

Frauke Muecksch

et al.

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

Published: June 30, 2023

Abstract The glycosylation of viral envelope proteins can play important roles in virus biology and immune evasion. spike (S) glycoprotein severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) includes 22 N-linked sequons 17 O-linked glycosites. Here, we investigated the effect individual sites on SARS-CoV-2 S function pseudotyped infection assays sensitivity to monoclonal polyclonal neutralizing antibodies. In most cases, removal decreased infectiousness virus. For mutants N-terminal domain (NTD) receptor binding (RBD), reduction pseudotype infectivity was predicted by a commensurate level virion-incorporated protein. Notably, presence glycan at position N343 within RBD had diverse effects neutralization RBD-specific antibodies (mAbs) cloned from convalescent individuals. reduced overall plasma COVID-19 individuals, suggesting role for However, vaccination individuals produced activity that resilient inhibitory glycan.

Language: Английский

Citations

3
Forty years of HIV research inspires the development of SARS-CoV-2 therapy DOI Creative Commons
Roberto Patarca, William A. Haseltine

Journal of Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 15(10)

Published: Oct. 1, 2023

Language: Английский

Citations

1
Enhanced surface accessibility of SARS-CoV-2 Omicron spike protein due to an altered glycosylation profile DOI Open Access
Dongxia Wang, Zijian Zhang,

Jakub Baudys

et al.

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

Published: Nov. 23, 2023

Abstract SARS-CoV-2 spike (S) proteins undergo extensive glycosylation, aiding proper folding, enhancing stability, and evading host immune surveillance. In this study, we used mass spectrometric analysis to elucidate the N-glycosylation characteristics disulfide bonding of recombinant derived from Omicron variant (B.1.1.529) in comparison with D614G variant. Furthermore, conducted microsecond-long molecular dynamics simulations on resolve how different N-glycans impact conformational sampling two variants. Our findings reveal that protein maintains an overall resemblance terms site-specific glycan processing bond formation. Nonetheless, alterations glycans were observed at certain sites. These changes, synergy mutations within protein, result increased surface accessibility macromolecule, including ectodomain, receptor-binding domain, N-terminal domain. insights contribute our understanding interplay between structure function, thereby advancing effective vaccination therapeutic strategies. Teaser Through spectrometry simulations, is found be less covered by when compared

Language: Английский

Citations

1
#GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern DOI Open Access
Callum M. Ives, Linh Nguyen, Carl A. Fogarty

et al.

Published: March 27, 2024

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

Citations

0
#GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern DOI Open Access
Callum M. Ives, Linh Nguyen, Carl A. Fogarty

et al.

Published: May 23, 2024

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

Citations

0