Omicron Spike Protein is Vulnerable to Reduction

Yao, Zhong; Geng, Betty; Marcon, Edyta; Pu, Shuye; Tang, Hua; Merluza, John; Bello, Alexander; Snider, Jamie; Lu, Ping; Wood, Heidi; Štagljar, Igor

doi:10.1016/j.jmb.2023.168128

Cited by 4 publications

(6 citation statements)

References 41 publications

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“…Thus, it is conceivable that the sequence and structure of these two spike protein variants may display better affinity for some receptors expressed at monocyte surface and/or may be capable to more intensely trigger monocyte activation and injury compared to the Omicron spike protein, as was earlier conjectured [35]. The lower chemical stability of the Omicron spike protein compared to the spike protein of former variants the has also been suggested as an important characteristic that may explain the lower pathogenetic burden of this strain [36].…”

Section: Discussionmentioning

confidence: 88%

Effects of Different Types of Recombinant SARS-CoV-2 Spike Protein on Circulating Monocytes Structure

Vettori¹,

Dima²,

Henry³

et al. 2023

Preprint

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Background: This study investigated the biological effects on circulating monocytes after challenge with SARS-CoV-2 recombinant spike protein. Methods: Whole blood collected form seven ostensibly healthy healthcare workers was incubated for 15 min with 2 and 20 ng/mL recombinant spike protein of Ancestral, Alpha, Delta and Omicron variants. Samples were analyzed with Sysmex XN and DI-60 analyzers. Results: Cellular complexity (i.e., presence of granules, vacuoles and other cytoplasmic inclusions) increased in all samples challenged with the recombinant spike protein of Ancestral, Alpha and Delta variants, but not in those containing Omicron. The cellular content of nucleic acids was constantly decreased in most samples, achieving statistical significance in those containing 20 ng/mL of Alpha and Delta recombinant spike proteins. The heterogeneity of monocyte volumes significantly increased in all samples, achieving statistical significance in those containing 20 ng/mL of recombinant spike protein of Ancestral, Alpha and Delta variants. The monocyte morphological abnormalities after spike protein challenge included dysmorphia, granulation, intense vacuolization, platelet phagocytosis, development of aberrant nuclei and cytoplasmic extrusions. Conclusions: The SARS-CoV-2 spike protein triggers important monocyte morphological abnormalities, more evident in cells challenged with spike protein of the more clinically severe Alpha and Delta variants.

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Section: Discussionmentioning

confidence: 88%

Effects of Different Types of Recombinant SARS-CoV-2 Spike Protein on Circulating Monocytes Structure

Vettori¹,

Dima²,

Henry³

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Fifteen disulfide bonds formed by 30 cysteine residues in the ectodomain of the S proteins have been visualized by three-dimensional structures and mass spectrometry. , Although these disulfide bonds are conserved in all variants of concerns, Yao et al have revealed that some disulfides in the RBD of the Omicron S protein, such as C480–C488 and C379–C432, are susceptible to reduction that could affect binding capacity and stability of the protein . To understand whether mutations of Omicron S affect the formation of disulfide bonds, we examined and compared the disulfide bonds of the S proteins of Omicron with the D614G variant using mass spectrometry analysis with four various enzyme digestion methods.…”

Section: Resultsmentioning

confidence: 99%

“…49 A recent study has revealed that mutations in the RBD domain of the Omicron S protein affect the stability of two disulfide bonds, elevating the vulnerability of this S variant to reduction. 50 Our aim in the present study was to better understand the structural characteristics and changes of the SARS-CoV-2 Omicron S protein (S-Omicron) relative to the S protein of the D614G variant (S-D614G). To do that, we used LC-MS to analyze the N-glycosylation profile and disulfide bonds for each, revealing distinct distributions of glycans at some sequons.…”

mentioning

confidence: 99%

“…Studies have shown that thiol-based drugs can impair the binding of S protein to ACE2, − and engineered disulfide bonds can trap S protein in an RBD “down” conformation. , The disulfide bond between C840 and C851 in the fusion peptide of S protein also can facilitate the binding between this peptide and cell membrane . A recent study has revealed that mutations in the RBD domain of the Omicron S protein affect the stability of two disulfide bonds, elevating the vulnerability of this S variant to reduction …”

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confidence: 99%

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confidence: 99%

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Enhanced Surface Accessibility of SARS-CoV-2 Omicron Spike Protein Due to an Altered Glycosylation Profile

Wang,

Zhang,

Baudys

et al. 2024

ACS Infect. Dis.

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SARS-CoV-2 spike (S) proteins undergo extensive glycosylation, aiding in proper folding, enhancing stability, and evading host immune surveillance. In this study, we used mass spectrometric analysis to elucidate the N-glycosylation characteristics and disulfide bonding of recombinant spike proteins derived from the SARS-CoV-2 Omicron variant (B.1.1.529) in comparison with the D614G spike variant. Furthermore, we conducted microsecond-long molecular dynamics simulations on spike proteins to resolve how the different N-glycans impact spike conformational sampling in the two variants. Our findings reveal that the Omicron spike protein maintains an overall resemblance to the D614G spike variant in terms of site-specific glycan processing and disulfide bond formation. Nonetheless, alterations in glycans were observed at certain N-glycosylation sites. These changes, in synergy with mutations within the Omicron spike protein, result in increased surface accessibility of the macromolecule, including the ectodomain, receptor-binding domain, and Nterminal domain. Additionally, mutagenesis and pull-down assays reveal the role of glycosylation of a specific sequon (N149); furthermore, the correlation of MD simulation and HDX-MS identified several high-dynamic areas of the spike proteins. These insights contribute to our understanding of the interplay between structure and function, thereby advancing effective vaccination and therapeutic strategies.

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Enhanced surface accessibility of SARS-CoV-2 Omicron spike protein due to an altered glycosylation profile

Wang,

Zhang,

Baudys

et al. 2023

Preprint

View full text Add to dashboard Cite

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

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Omicron Spike Protein is Vulnerable to Reduction

Cited by 4 publications

References 41 publications

Effects of Different Types of Recombinant SARS-CoV-2 Spike Protein on Circulating Monocytes Structure

Effects of Different Types of Recombinant SARS-CoV-2 Spike Protein on Circulating Monocytes Structure

Enhanced Surface Accessibility of SARS-CoV-2 Omicron Spike Protein Due to an Altered Glycosylation Profile

Enhanced surface accessibility of SARS-CoV-2 Omicron spike protein due to an altered glycosylation profile

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