<i>In silico</i>study on the effects of disulfide bonds in ORF8 of SARS-CoV-2

Cheng, Yadi; Peng, Xubiao

doi:10.1039/d2cp01724e

Cited by 6 publications

(10 citation statements)

References 52 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Concordantly, an early study showed that ORF8 downregulates MHC-I by binding and targeting this immune receptor for lysosomal degradation, as a result protecting SARS-CoV-2-infected cells from CTL killing [11], which was corroborated by other reports [34,70]. In silico analysis further predicted that the main sites in ORF8 which mediate its binding to MHC-I involve positions 39-42 (IHFY), 104-107 (FYED), and 110-112 (EYH), while the deletion of positions 119-120 in the ORF8 of SARS-CoV-2 variant Delta decreases binding compared to wild-type ORF8 [84]. Downregulation of antigen presentation by SARS-CoV-2 was further expanded on by studies from other groups demonstrating that ORF3a, ORF6, and ORF7a are also potent viral antagonists of MHC-I signaling [83,85,86].…”

Section: Downregulation Of Mhc-i To Counter the Ctl Responsesupporting

confidence: 80%

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

Arduini

Laprise

Liang

2023

Viruses

View full text Add to dashboard Cite

The COVID-19 pandemic has resulted in upwards of 6.8 million deaths over the past three years, and the frequent emergence of variants continues to strain global health. Although vaccines have greatly helped mitigate disease severity, SARS-CoV-2 is likely to remain endemic, making it critical to understand its viral mechanisms contributing to pathogenesis and discover new antiviral therapeutics. To efficiently infect, this virus uses a diverse set of strategies to evade host immunity, accounting for its high pathogenicity and rapid spread throughout the COVID-19 pandemic. Behind some of these critical host evasion strategies is the accessory protein Open Reading Frame 8 (ORF8), which has gained recognition in SARS-CoV-2 pathogenesis due to its hypervariability, secretory property, and unique structure. This review discusses the current knowledge on SARS-CoV-2 ORF8 and proposes actualized functional models describing its pivotal roles in both viral replication and immune evasion. A better understanding of ORF8’s interactions with host and viral factors is expected to reveal essential pathogenic strategies utilized by SARS-CoV-2 and inspire the development of novel therapeutics to improve COVID-19 disease outcomes.

show abstract

Section: Downregulation Of Mhc-i To Counter the Ctl Responsesupporting

confidence: 80%

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

Arduini

Laprise

Liang

2023

Viruses

View full text Add to dashboard Cite

show abstract

“…A similar RMSF profile and the considerably higher flexibility of β4-β5 loop region were previously observed in MD studies on ORF8 dimer structures ( Chaudhari et al, 2023 ; Islam et al, 2023 ; Selvaraj et al, 2023 ). These flexible regions were suggested as functional regions that may play major roles in protein-protein interactions in past studies ( Wang et al, 2021 ; Cheng and Peng, 2022 ; Arduini et al, 2023 ). These regions may undergo conformational changes during their functional processes.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the examination of the secondary structure further emphasizes the inherent flexibility of the β4-β5 loop, which serves as a critical mediator of interactions in both the tetrameric and trimeric configurations of ORF8. It has been observed that the manipulation of disulfide bonds can impact the conformation of the β4-β5 loop segments ( Cheng and Peng, 2022 ). Further studies can investigate the ORF8 multimeric forms about the oxidative and reductive environments.…”

Section: Discussionmentioning

confidence: 99%

“…In the structure of 121-amino acid ORF8, an Ig-like domain follows a 15-amino acid signal peptide at the N-terminus. Reducing the three intramolecular disulfide bonds that hold the eight antiparallel ß-strands together that the Ig-like domain folds into has been shown to have a negligible impact on the system’s overall characteristics ( Cheng and Peng, 2022 ). ORF8 structure is experimentally obtained as a covalently bonded dimer by X-ray crystallography ( Flower et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oligomer formation of SARS-CoV-2 ORF8 through 73YIDI76 motifs regulates immune response and non-infusion antiviral interactions

Assadizadeh,

Azimzadeh Irani

2023

Front. Mol. Biosci.

View full text Add to dashboard Cite

Introduction: Open Reading Frame 8 (ORF8) is a 121 amino acid length SARS-CoV-2 specific accessory protein that plays crucial roles in viral infectivity, and pathogenesis. Current SARS-CoV-2 treatments focus on spike or RNA-dependent RNA polymerase proteins. Hence, directing attention to ORF8 yields substantial benefits for innovative non-infusional therapeutics. Functional ORF8 is proposed to form oligomers via a crystallographic contact centered by 73YIDI76 motifs.Methods: Hence, the structure and atomistic interactions of trimeric and tetrameric ORF8 oligomeric forms were modeled by means of thorough molecular modeling and molecular dynamics simulations.Results: Results show that trimeric and tetrameric oligomers are stabilized by the interaction of β4-β5 (47-83) loops. 73YIDI76 motifs are involved in obtaining the oligomerization interfaces. It is shown that the tetramers which resemble a doughnut-like construction are the most stabilized oligomeric forms. Where four β4-β5 loops form the interfaces between two dimers. Each monomer links to two others through β4-β5 loops and a covalent Cys20-Cys20 bridge. Epitope mapping, binding site predictions, and solvent-accessible surface area analyses of different ORF8 forms show that the B-cell, MHC-I, and drug epitopes stay exposed in oligomeric forms.Discussion: Approving that the viral infectivity is expanded upon ORF8 oligomerization and the regions involved in oligomerization can be considered as therapeutic targets.

show abstract

“…The configuration of ORF8 intramolecular disulfide bonds was also suggested to be sensitive to the nature and conformation of the residues adjacent to the Cys residues ( 27 ), which notably are often variant sites such as residues 24, 26, 62, and 84. Finally, an in silico study indicated that the structure of ORF8, especially the loop regions, was greatly influenced by the status of the intramolecular disulfide bonds ( 59 ). The disulfide bonds may therefore represent another structural element associated with conformational adaptability in ORF8.…”

Section: Structure-function Relationshipmentioning

confidence: 99%

SARS-CoV-2 ORF8: One protein, seemingly one structure, and many functions

Vinjamuri

Bouvier

2022

Front. Immunol.

View full text Add to dashboard Cite

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. The genome of SARS-CoV-2 encodes nine accessory proteins that are involved in host-pathogen interaction. ORF8 is unique among these accessory proteins. SARS-CoV-2 ORF8 shares a surprisingly low amino acid sequence similarity with SARS-COV ORF8 (30%), and it is presumed to have originated from bat. Studies have shown that ORF8 exerts multiple different functions that interfere with host immune responses, including the downregulation of MHC class I molecules. These functions may represent strategies of host immune evasion. The x-ray crystal structure of ORF8 revealed an immunoglobulin-like domain with several distinguishing features. To date, there are numerous unanswered questions about SARS-CoV-2 ORF8 protein and its structure-function relationship that we discuss in this mini-review. A better understanding of how ORF8 interacts with components of the immune system is needed for elucidating COVID-19 pathogenesis and to develop new avenues for the treatment of the disease.

show abstract

In silicostudy on the effects of disulfide bonds in ORF8 of SARS-CoV-2

Abstract: The COVID-19 epidemic, caused by virus SARS-CoV-2, has been a pandemic and threatening everyone's health in the past two years. In SARS-CoV-2, ORF8 is one of the most important accessory...

Cited by 6 publications

References 52 publications

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

SARS-CoV-2 ORF8: A Rapidly Evolving Immune and Viral Modulator in COVID-19

Oligomer formation of SARS-CoV-2 ORF8 through 73YIDI76 motifs regulates immune response and non-infusion antiviral interactions

SARS-CoV-2 ORF8: One protein, seemingly one structure, and many functions

Contact Info

Product

Resources

About