Dataset Information

Site specific N-linked glycosylation analysis of spike proteins of SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63, and HCoV-229E

ABSTRACT: Site specific N-linked glycosylation analysis of spike proteins of SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63, and HCoV-229E

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Shang-Te Danny Hsu

PROVIDER: MSV000092889 | MassIVE |

REPOSITORIES: MassIVE

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Publications

Rapid simulation of glycoprotein structures by grafting and steric exclusion of glycan conformer libraries.

Tsai Yu-Xi YX Chang Ning-En NE Reuter Klaus K Chang Hao-Ting HT Yang Tzu-Jing TJ von Bülow Sören S Sehrawat Vidhi V Zerrouki Noémie N Tuffery Matthieu M Gecht Michael M Grothaus Isabell Louise IL Colombi Ciacchi Lucio L Wang Yong-Sheng YS Hsu Min-Feng MF Khoo Kay-Hooi KH Hummer Gerhard G Hsu Shang-Te Danny SD Hanus Cyril C Sikora Mateusz M

Cell 20240201 5

Most membrane proteins are modified by covalent addition of complex sugars through N- and O-glycosylation. Unlike proteins, glycans do not typically adopt specific secondary structures and remain very mobile, shielding potentially large fractions of protein surface. High glycan conformational freedom hinders complete structural elucidation of glycoproteins. Computer simulations may be used to model glycosylated proteins but require hundreds of thousands of computing hours on supercomputers, thus ...[more]

PMID: 38428397

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Project description:Despite the clinical success of anti-spike vaccines, the effectiveness of neutralizing antibodies and vaccines by rapidly spreading SARS-CoV-2 variants has been compromised. Viruses can hijack the glycosylation machinery of host cells to shield themselves from the host’s immune response and attenuate antibody efficiency. However, it still remains unclear whether targeting glycosylation on spike can impair SARS-CoV-2 and its variants infectivity. Methods: To assess the binding ability of glycosylated or deglycosylated spike with ACE2, we performed flow cytometry, ELISA, and BioLayer Interferometry methods. Viral entry ability was determined by luciferase intensity, immunoblotting, and immunofluorescence assay. A genome-wide association study (GWAS) was performed to identify the relationship of STT3A and COVID-19 severity. N-glycosylation regulated by NF-kB/STT3A axis was investigated by knockdown approach, chromatin immunoprecipitation, and promoter assay. To specifically target SARS-CoV-2 infected cells, we developed an antibody-drug conjugate coupling non-neutralization anti-spike antibody with NGI-1 (4G10-ADC) on inhibitory effects of SARS-CoV-2 infection. Results: We found receptor binding domain and three SARS-CoV-2 distinct surface Nglycosylation sites in 57,311 spikes retrieved from NCBI-Virus-database are highly evolutionarily conserved (99.67%) and involved in ACE2 interaction. We further identified STT3A as a key glycosyltransferase that catalyzed spike glycosylation and positively correlated with COVID-19 severity. Inhibition of STT3A by N-linked glycosylation inhibitor-1 (NGI-1) impaired SARS-CoV-2 and its variants (B.1.1.7, and B.1.351) infectivity. Most importantly, 4G10-ADC internalized SARS-CoV-2 infected cells and subsequently released NGI-1 to deglycosylate spike protein. Thereby, it reinforces the neutralizing abilities in antibodies, vaccines, or convalescent sera, inhibiting SARS-CoV-2 and its variants’ infectivity. Our results suggest targeting STT3A-mediated evolution conserved glycosylation via ADC can provide a widespread impact on SARS-CoV-2 variants infection. Together, we identified a novel deglycosylation method to eradicate SARS-CoV-2 variants infection.