Glycan shield of the ebolavirus envelope glycoprotein GP

Peng, Weiwei; Rayaprolu, Vamseedhar; Parvate, Amar; Hui, Sean; Parekh, Diptiben; Yu, Xiaoying; Saphire, Erica Ollmann; Snijder, Joost

doi:10.1038/s42003-022-03767-1

Cited by 17 publications

(14 citation statements)

References 89 publications

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“…These results both validate our model and propose mechanisms for evolutionary control over the viral glycan shield. 11,25,100,101 Across three SARS-CoV-2 Variants of Concern, we show that high glycoimpact variations close to glycosites produce IMR-consistent differential spike glycosylation. If IMR can predict differential glycosylation as viruses evolve, these predictions could help predict immune evasion and predict the viral evolutionary landscape for many viruses.…”

Section: Discussionmentioning

confidence: 67%

Protein structure, a genetic encoding for glycosylation

Kellman,

Sandoval,

Zaytseva

et al. 2024

Preprint

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DNA, RNA, and proteins are synthesized using template molecules, but glycosylation is not believed to be constrained by a template. However, if cellular environment is the only determinant of glycosylation, all sites should receive the same glycans on average. This template-free assertion is inconsistent with observations of microheterogeneity-wherein each site receives distinct and reproducible glycan structures. Here, we test the assumption of template-free glycan biosynthesis. Through structural analysis of site-specific glycosylation data, we find protein-sequence and structural features that predict specific glycan features. To quantify these relationships, we present a new amino acid substitution matrix that describes glycoimpact-how glycosylation varies with protein structure. High-glycoimpact amino acids co-evolve with glycosites, and glycoimpact is high when estimates of amino acid conservation and variant pathogenicity diverge. We report hundreds of disease variants near glycosites with high-glycoimpact, including several with known links to aberrant glycosylation (e.g., Oculocutaneous Albinism, Jakob-Creutzfeldt disease, Gerstmann-Straussler-Scheinker, and Gaucher's Disease). Finally, we validate glycoimpact quantification by studying oligomannose-complex glycan ratios on HIV ENV, differential sialylation on IgG3 Fc, differential glycosylation on SARS-CoV-2 Spike, and fucose-modulated function of a tuberculosis monoclonal antibody. In all, we show glycan biosynthesis is accurately guided by specific, genetically-encoded rules, and this presents a plausible refutation to the assumption of template-free glycosylation.

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Section: Discussionmentioning

confidence: 67%

Protein structure, a genetic encoding for glycosylation

Kellman,

Sandoval,

Zaytseva

et al. 2024

Preprint

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“…However, RAVV GP structure is more stable compared to MARV GP (29). Our results suggest that sequence evolution may in uence a structural divergence between the GPs of distant marburgviruses by potentially affecting stability, modi cations (37) and/or the spatial location of domains. The crystal structures of GP from closely related ebolaviruses, EBOV and SUDV, highlighted electrostatic differences which may be responsible for their opposing susceptibility to endosomal proteases (38).…”

Section: Discussionmentioning

confidence: 76%

Divergent antibody recognition profiles are generated by protective mRNA vaccines against Marburg and Ravn viruses.

Bukreyev,

Meyer,

Gunn

et al. 2024

Preprint

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The first-ever recent Marburg virus (MARV) outbreak in Ghana, West Africa and Equatorial Guinea has refocused efforts towards the development of therapeutics since no vaccine or treatment has been approved. mRNA vaccines were proven successful in a pandemic-response to severe acute respiratory syndrome coronavirus-2, making it an appealing vaccine platform to target highly pathogenic emerging viruses. Here, 1-methyl-pseudouridine-modified mRNA vaccines formulated in lipid nanoparticles (LNP) were developed against MARV and the closely-related Ravn virus (RAVV), which were based on sequences of the glycoproteins (GP) of the two viruses. Vaccination of guinea pigs with both vaccines elicited robust binding and neutralizing antibodies and conferred complete protection against virus replication, disease and death. The study characterized antibody responses to identify disparities in the binding and functional profiles between the two viruses and regions in GP that are broadly reactive. For the first time, the glycan cap is highlighted as an immunoreactive site for marburgviruses, inducing both binding and neutralizing antibody responses that are dependent on the virus. Profiling the antibody responses against the two viruses provided an insight into how antigenic differences may affect the response towards conserved GP regions which would otherwise be predicted to be cross-reactive and has implications for the future design of broadly protective vaccines. The results support the use of mRNA-LNPs against pathogens of high consequence.

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“…These include a combination of truncated Tn‐antigen and extended, sialylated core 1 and 2 structures. Additionally, they have identified several O‐glycosylation sites outside the MLD of EBOV GP, such as Thr280 and Thr206 53 . Interestingly, upon infection of host cells with EBOV, there was a significant decrease in endothelial cell adhesion induced by the surface GP.…”

Section: The Roles Of O‐glycosylation In Rna Virusesmentioning

confidence: 99%

O‐glycosylation in viruses: A sweet tango

Ming,

Zhao,

Liu

et al. 2024

mLife

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O‐glycosylation is an ancient yet underappreciated protein posttranslational modification, on which many bacteria and viruses heavily rely to perform critical biological functions involved in numerous infectious diseases or even cancer. But due to the innate complexity of O‐glycosylation, research techniques have been limited to study its exact role in viral attachment and entry, assembly and exit, spreading in the host cells, and the innate and adaptive immunity of the host. Recently, the advent of many newly developed methodologies (e.g., mass spectrometry, chemical biology tools, and molecular dynamics simulations) has renewed and rekindled the interest in viral‐related O‐glycosylation in both viral proteins and host cells, which is further fueled by the COVID‐19 pandemic. In this review, we summarize recent advances in viral‐related O‐glycosylation, with a particular emphasis on the mucin‐type O‐linked α‐N‐acetylgalactosamine (O‐GalNAc) on viral proteins and the intracellular O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) modifications on host proteins. We hope to provide valuable insights into the development of antiviral reagents or vaccines for better prevention or treatment of infectious diseases.

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Glycan shield of the ebolavirus envelope glycoprotein GP

Cited by 17 publications

References 89 publications

Protein structure, a genetic encoding for glycosylation

Protein structure, a genetic encoding for glycosylation

Divergent antibody recognition profiles are generated by protective mRNA vaccines against Marburg and Ravn viruses.

O‐glycosylation in viruses: A sweet tango

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