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Structural biology of SARS-CoV-2 accessory proteins

CRYSTALLOGRAPHY REVIEWS (2023)

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Article Biochemistry & Molecular Biology

SARS-CoV-2 accessory protein ORF8 is secreted extracellularly as a glycoprotein homodimer

Kazuhiro Matsuoka et al.

Summary: This study established an ORF8 expression system in 293T cells and found that ORF8 exists as a secreted homodimer. The expression of ORF8 does not affect the total amounts of MHC-I, ACE2, and CoV-2 S proteins, but reduces the expression of cell surface MHC-I protein. Additionally, ORF8 does not have significant stimulatory effects in human macrophages.

JOURNAL OF BIOLOGICAL CHEMISTRY (2022)

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Article Biotechnology & Applied Microbiology

SignalP 6.0 predicts all five types of signal peptides using protein language models

Felix Teufel et al.

Summary: Signal peptides are short amino acid sequences that regulate protein secretion and translocation. SignalP 6.0, a machine learning model, is introduced to detect all types of signal peptides, including those applicable to metagenomic data.

NATURE BIOTECHNOLOGY (2022)

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Article Biochemistry & Molecular Biology

Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1-Nup98 Complex to Compete With mRNA Nuclear Export

Tinghan Li et al.

Summary: The study investigates the role and mechanism of accessory protein Orf6 in the inhibition of host interferon signaling in coronaviruses. Orf6 interacts with the Rae1-Nup98 complex to inhibit the nuclear export of mRNA. The results show that SARS-CoV Orf6 occupies the potential mRNA-binding groove of the Rae1-Nup98 complex, and the highly conserved methionine (M58) in SARS-CoVs Orf6 plays a critical role.

FRONTIERS IN MOLECULAR BIOSCIENCES (2022)

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Article Microbiology

Viral Mimicry of Interleukin-17A by SARS-CoV-2 ORF8

Xin Wu et al.

Summary: Patients infected with SARS-CoV-2 variants lacking open reading frame 8 (ORF8) have milder infection and disease outcome. The study reveals that secreted ORF8 protein mimics host IL-17 to activate IL-17 receptors A and C, inducing a stronger inflammatory response than host IL-17A. This provides molecular insights into the role of ORF8 in COVID-19 pathogenesis and serves as a potential therapeutic target.

MBIO (2022)

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Article Microbiology

The ORF8 Protein of SARS-CoV-2 Modulates the Spike Protein and Its Implications in Viral Transmission

Jen-Mei Chou et al.

Summary: This article reports on the strong potency of the accessory protein ORF8 in modulating the level and processing of the spike protein in SARS-CoV-2. ORF8 expression leads to downregulation and insufficient cleavage of the spike protein, potentially reducing the virus's infection potential.

FRONTIERS IN MICROBIOLOGY (2022)

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Article Multidisciplinary Sciences

SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry

John Kee et al.

Summary: Research reveals that the ORF8 protein of SARS-CoV-2 functions as a mimic of histone H3, disrupting the epigenetic regulation of host cells. This finding provides insight into how SARS-CoV-2 controls host cell epigenome and sheds light on the association between the absence of ORF8 and decreased severity of COVID-19.

NATURE (2022)

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Article Biochemistry & Molecular Biology

Overexpression of SARS-CoV-2 protein ORF6 dislocates RAE1 and NUP98 from the nuclear pore complex

Koki Kato et al.

Summary: Studies have shown that the ORF6 protein of SARS-CoV-2 can manipulate the localization and functions of nucleoporins, leading to abnormal nucleocytoplasmic trafficking and ultimately reducing the size of host cell nucleus and halting cell growth.

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (2021)

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Letter Immunology

Ubiquitination of SARS-CoV-2 ORF7a promotes antagonism of interferon response

Zengguo Cao et al.

CELLULAR & MOLECULAR IMMUNOLOGY (2021)

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Article Cell Biology

ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation

Guangyan Miao et al.

Summary: ORF3a of the COVID-19 virus SARS-CoV-2 inhibits autophagy activity by blocking fusion of autophagosomes/amphisomes with lysosomes. This leads to accumulation of autophagosomes/amphisomes, impaired lysosome function, and ultimately blocks autophagy process.

DEVELOPMENTAL CELL (2021)

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Article Infectious Diseases

Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom, October to November 2020

Kathy Leung et al.

Summary: Two new lineages of SARS-CoV-2 with the N501Y mutation in the receptor-binding domain of the spike protein have spread rapidly in the United Kingdom. The 501Y lineage without amino acid deletion Delta 69/Delta 70 was estimated to be 10% more transmissible than the 501N lineage, while the 501Y lineage with amino acid deletion Delta 69/Delta 70 was estimated to be 75% more transmissible than the 501N lineage.

EUROSURVEILLANCE (2021)

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Article Biochemistry & Molecular Biology

UniProt: the universal protein knowledgebase in 2021

Alex Bateman et al.

Summary: The UniProt Knowledgebase aims to provide users with a comprehensive, high-quality set of protein sequences annotated with functional information. Updates over the past two years have increased the number of sequences to approximately 190 million, with new methods to assess proteome completeness and quality. UniProtKB has responded to the COVID-19 pandemic by expertly curating relevant entries and making them rapidly available through a dedicated portal.

NUCLEIC ACIDS RESEARCH (2021)

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Article Multidisciplinary Sciences

Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein

Thomas G. Flower et al.

Summary: The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-angstrom resolution by X-ray crystallography, revealing unique dimerization interfaces that may allow the protein to form large-scale assemblies, potentially mediating immune suppression and evasion activities.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2021)

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Article Infectious Diseases

Different mutations in SARS-CoV-2 associate with severe and mild outcome

Adam Nagy et al.

Summary: The study found a correlation between protein-level mutations in the SARS-CoV-2 virus and clinical outcomes, with some mutations associated with severe disease.

INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS (2021)

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Article Multidisciplinary Sciences

SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis

Ji-Seung Yoo et al.

Summary: The authors show that SARS-CoV-2 targets key transcriptional regulators of the MHC class I pathway to hinder antigen presentation, revealing an immune evasion mechanism that suppresses host immune response.

NATURE COMMUNICATIONS (2021)

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Article Multidisciplinary Sciences

Structural insight reveals SARS-CoV-2 ORF7a as an immunomodulating factor for human CD14+ monocytes

Ziliang Zhou et al.

Summary: SARS-CoV-2 ORF7a interacts efficiently with human CD14(+) monocytes, triggering inflammatory responses such as decreased HLA expression and increased production of proinflammatory cytokines. This suggests that ORF7a may be a key immunomodulating factor in the severe immune response seen in COVID-19 patients.

ISCIENCE (2021)

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Article Multidisciplinary Sciences

ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway

Xiaoyuan Lin et al.

Summary: This study showed that the ORF8 protein of SARS-CoV-2 can induce cytokine storm, with IL-17 signaling pathway playing a crucial role in this process. Treatment with IL17RA antibody can protect mice from ORF8-induced inflammation, providing a potential target for the development of COVID-19 therapeutic drugs.

ISCIENCE (2021)

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Article Immunology

Crystal Structures of Bat and Human Coronavirus ORF8 Protein Ig-Like Domain Provide Insights Into the Diversity of Immune Responses

Xiaoxue Chen et al.

Summary: The study determined the crystal structures of SARS-CoV-2 ORF8 (S84) and bat coronavirus RaTG13 ORF8 variant, revealing differences in conformations of residues in the Ig-like domain. It was found that the Cys20 residue in ORF8 is responsible for forming the covalent disulfide-linked dimer in crystal packing and in vitro biochemical conditions. Additionally, immune cell-binding assays showed different interaction capabilities of various ORF8 proteins with human CD14(+) monocytes, suggesting potential influence on disease-related immune responses.

FRONTIERS IN IMMUNOLOGY (2021)

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Article Biochemistry & Molecular Biology

Functional landscape of SARS-CoV-2 cellular restriction

Laura Martin-Sancho et al.

Summary: This study identified specific ISGs that control viral replication and assembly/release of SARS-CoV-2, including BST2/tetherin, offering insights into host determinants impacting disease severity and potential therapeutic strategies for COVID-19.

MOLECULAR CELL (2021)

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Article Multidisciplinary Sciences

Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV

Alexey Stukalov et al.

Summary: The study reports a concurrent multi-omics analysis of SARS-CoV-2 and SARS-CoV, revealing both distinct and common molecular mechanisms between these closely related coronaviruses, as well as their impact on the host cell proteome. The results of this study may provide insights into the design of virus- and host-directed therapies for these coronaviruses.

NATURE (2021)

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Article Microbiology

SARS-CoV-2 ORF6 Disrupts Bidirectional Nucleocytoplasmic Transport through Interactions with Rae1 and Nup98

Amin Addetia et al.

Summary: SARS-CoV-2 infection results in the accumulation of nuclear mRNA, attributed to the accessory protein ORF6 which interacts with Rae1 and Nup98 to trap host mRNA in the nucleus. Both SARS-CoV and SARS-CoV-2 ORF6 block the nuclear import of host proteins through interactions with Rae1 and Nup98, potentially preventing host cells from responding to viral infection.

MBIO (2021)

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Article Multidisciplinary Sciences

Crystal structure of SARS-CoV-2 Orf9b in complex with human TOM70 suggests unusual virus-host interactions

Xiaopan Gao et al.

Summary: Orf9b, a unique accessory protein of SARS-CoV-2 and SARS-CoV, interacts with TOM70 to potentially interfere with immunity and suppress interferon responses by inhibiting the Hsp90/TOM70 interaction. The specific mechanisms of these interactions shed light on the pathogenesis of these coronaviruses.

NATURE COMMUNICATIONS (2021)

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Article Biochemistry & Molecular Biology

Characterization of SARS-CoV-2 proteins reveals Orf6 pathogenicity, subcellular localization, host interactions and attenuation by Selinexor

Jin-Gu Lee et al.

Summary: This study identified Orf6 as a highly pathogenic protein in the SARS-CoV-2 genome and its interaction with key host proteins. The drug Selinexor was found to attenuate Orf6-induced cellular toxicity, suggesting it as a potential candidate for targeting Orf6 host protein interactions that lead to cytotoxicity.

CELL AND BIOSCIENCE (2021)

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Article Virology

Contribution of SARS-CoV-2 Accessory Proteins to Viral Pathogenicity in K18 Human ACE2 Transgenic Mice

Jesus A. Silvas et al.

Summary: The study identified ORF3a and ORF6 as major contributors to viral pathogenesis in SARS-CoV-2, while ORF7a, ORF7b, and ORF8 had little impact on disease outcome. Additionally, the use of a reverse-genetics system to generate recombinant SARS-CoV-2 constructs lays the foundation for developing live attenuated vaccines for the treatment of SARS-CoV-2.

JOURNAL OF VIROLOGY (2021)

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Article Multidisciplinary Sciences

Highly accurate protein structure prediction with AlphaFold

John Jumper et al.

Summary: Proteins are essential for life, and accurate prediction of their structures is a crucial research problem. Current experimental methods are time-consuming, highlighting the need for accurate computational approaches to address the gap in structural coverage. Despite recent progress, existing methods fall short of atomic accuracy in protein structure prediction.

NATURE (2021)

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Article Microbiology

SARS-CoV-2 Accessory Protein ORF7b Mediates Tumor Necrosis Factor-α-Induced Apoptosis in Cells

Ruiping Yang et al.

Summary: In this study, it was found that the accessory protein ORF7b of SARS-CoV-2 promoted the expression of IFN-beta, TNF-alpha, and IL-6, activated the type-I interferon signaling pathway through IRF3 phosphorylation, and induced TNF alpha-induced apoptosis in HEK293T and Vero E6 cells. These findings provide insights into the pathogenicity of SARS-CoV-2 and the interaction between ORF7b and host immune responses.

FRONTIERS IN MICROBIOLOGY (2021)

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Article Biochemical Research Methods

The Protein Imager: a full-featured online molecular viewer interface with server-side HQ-rendering capabilities

Gianluca Tomasello et al.

BIOINFORMATICS (2020)

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Article Immunology

Extended ORF8 Gene Region Is Valuable in the Epidemiological Investigation of Severe Acute Respiratory Syndrome-Similar Coronavirus

Shuaiyin Chen et al.

JOURNAL OF INFECTIOUS DISEASES (2020)

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Review Biochemistry & Molecular Biology

The molecular virology of coronaviruses

Ella Hartenian et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2020)

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Article Multidisciplinary Sciences

SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling

Lisa Miorin et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2020)

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Article Multidisciplinary Sciences

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms

David E. Gordon et al.

SCIENCE (2020)

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Article Cell Biology

Evasion of Type I Interferon by SARS-CoV-2

Hongjie Xia et al.

CELL REPORTS (2020)

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Article Biochemistry & Molecular Biology

Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC

Kam-Leung Siu et al.

FASEB JOURNAL (2019)

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Review Immunology

The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Karen V. Swanson et al.

NATURE REVIEWS IMMUNOLOGY (2019)

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Article Biochemistry & Molecular Biology

JPred4: a protein secondary structure prediction server

Alexey Drozdetskiy et al.

NUCLEIC ACIDS RESEARCH (2015)

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Review Microbiology

Coronaviruses post-SARS: update on replication and pathogenesis

Stanley Perlman et al.

NATURE REVIEWS MICROBIOLOGY (2009)

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Article Virology

Severe acute respiratory syndrome coronavirus accessory protein 9b is a virion-associated protein

Ke Xu et al.

VIROLOGY (2009)

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Review Biochemistry & Molecular Biology

Inference of macromolecular assemblies from crystalline state

Evgeny Krissinel et al.

JOURNAL OF MOLECULAR BIOLOGY (2007)

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Article Virology

The ORF7b protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is expressed in virus-infected cells and incorporated into SARS-CoV particles

Scott R. Schaecher et al.

JOURNAL OF VIROLOGY (2007)

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Article Biochemistry & Molecular Biology

The crystal structure of ORF-9b, a lipid binding protein from the SARS coronavirus

Christoph Meier et al.

STRUCTURE (2006)

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Review Immunology

Type I inteferon gene induction by the interferon regulatory factor family of transcription factors

Kenya Honda et al.

IMMUNITY (2006)

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