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ORF7a

Betacoronavirus NS7A protein
Structure of the SARS-coronavirus ORF7a accessory protein
Identifiers
SymbolbCoV_NS7A
PfamPF08779
InterProIPR014888
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

ORF7a (also known by several other names, including SARS coronavirus X4, SARS-X4, ORF7a, or U122)[1] is a gene found in coronaviruses of the Betacoronavirus genus. It expresses the Betacoronavirus NS7A protein, a type I transmembrane protein with an immunoglobulin-like protein domain. It was first discovered in SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS).[2] The homolog in SARS-CoV-2, the virus that causes COVID-19, has about 85% sequence identity to the SARS-CoV protein.[3]

Function

A number of possible functions for the ORF7a protein have been described. The primary function is thought to be immunomodulation and interferon antagonism. The protein is not essential for viral replication.[1]

Viral protein interactions

Studies in SARS-CoV suggest that the protein forms protein-protein interactions with spike protein and ORF3a, and is present in mature virions, making it a minor viral structural protein.[1][4] It is unclear if this occurs in SARS-CoV-2.[5] It may have a role in viral assembly.[1]

Host effects

A number of interactions with host proteins and effects on host cell processes have been described. The SARS-CoV ORF7a protein has been reported to have binding activity to integrin I domains.[6]

It has also been reported to induce apoptosis via a caspase dependent pathway.[1][7] Also, it contains a motif which has been demonstrated to mediate COPII dependent transport out of the endoplasmic reticulum, and the protein is targeted to the Golgi apparatus.[8]

In SARS-CoV-2, ORF7a protein has been described as an effective interferon antagonist.[3] The SARS-CoV-2 protein may have immunomodulatory effects through interaction with monocytes.[5]

Structure

The ORF7a protein is a transmembrane protein with 121 amino acid residues in SARS-CoV-2[5] and 122 in SARS-CoV.[2] It is a type I transmembrane protein with an N-terminal signal peptide, an ectodomain that has an immunoglobulin fold, and a C-terminal endoplasmic reticulum retention signal sequence.[5][6][1] The structure contains seven beta strands which form two beta sheets, arranged in a beta sandwich.[2] Most of the sequence differences between SARS-CoV and SARS-CoV-2 occur in the Ig-like ectodomain and may produce differences in protein-protein interactions.[5]

Post-translational modifications

The SARS-CoV-2 ORF7a protein has been reported to be post-translationally modified by ubiquitination. Polyubiquitin chains attached to lysine 119 may be related to the protein's reported interferon antagonism.[3][9]

Expression and localization

Genomic information
Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2, indicating the location of ORF7a
NCBI genome ID86693
Genome size29,903 bases
Year of completion2020
Genome browser (UCSC)

Along with the genes for other viral accessory proteins, the ORF7a gene is located near those encoding the viral structural proteins, at the 5' end of the coronavirus RNA genome.[3] ORF7a is an overlapping gene that overlaps ORF7b.[10] In SARS-CoV, subcellular localization to the endoplasmic reticulum, Golgi apparatus, and ERGIC has been reported,[1] with similar Golgi localization described for SARS-CoV-2.[11]

Evolution

Structural superposition of the Ig domains of ORF8 (blue, PDB: 7JTL​[12]) and ORF7a (orange, PDB: 7CI3​[5]) illustrating the similarity of their beta-sandwich topologies.

It is thought that ORF8 in SARS-CoV-2, which encodes a protein with a similar Ig-like fold, may be a paralog of ORF7a that originated through gene duplication,[13][14] though some bioinformatics analyses suggest the similarity may be too low to support duplication, which is relatively uncommon in viruses.[15] Immunoglobulin domains are uncommon in coronaviruses; other than the subset of betacoronaviruses with ORF8 and ORF7a, only a small number of bat alphacoronaviruses have been identified as containing likely Ig domains, while they are absent from gammacoronaviruses and deltacoronaviruses.[16][14] The beta and alpha Ig domains may be independent acquisitions, where ORF8 and ORF7a may have been acquired from host proteins.[16]

Many SARS-CoV-2 genomes have been sequenced throughout the COVID-19 pandemic and a number of variations have been reported, including deletion mutations,[17] nonsense mutations (introducing a premature stop codon and truncating the protein),[18] and at least one gene fusion.[19]

References

  1. ^ a b c d e f g Liu, DX; Fung, TS; Chong, KK; Shukla, A; Hilgenfeld, R (September 2014). "Accessory proteins of SARS-CoV and other coronaviruses". Antiviral Research. 109: 97–109. doi:10.1016/j.antiviral.2014.06.013. PMC 7113789. PMID 24995382.
  2. ^ a b c Nelson CA, Pekosz A, Lee CA, Diamond MS, Fremont DH (2005). "Structure and intracellular targeting of the SARS-coronavirus Orf7a accessory protein". Structure. 13 (1): 75–85. doi:10.1016/j.str.2004.10.010. PMC 7125549. PMID 15642263.
  3. ^ a b c d Redondo, Natalia; Zaldívar-López, Sara; Garrido, Juan J.; Montoya, Maria (7 July 2021). "SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns". Frontiers in Immunology. 12: 708264. doi:10.3389/fimmu.2021.708264. hdl:10261/249329. PMC 8293742. PMID 34305949.
  4. ^ Huang, Cheng; Ito, Naoto; Tseng, Chien-Te K.; Makino, Shinji (August 2006). "Severe Acute Respiratory Syndrome Coronavirus 7a Accessory Protein Is a Viral Structural Protein". Journal of Virology. 80 (15): 7287–7294. doi:10.1128/JVI.00414-06. PMC 1563709. PMID 16840309.
  5. ^ a b c d e f Zhou, Ziliang; Huang, Chunliu; Zhou, Zhechong; Huang, Zhaoxia; Su, Lili; Kang, Sisi; Chen, Xiaoxue; Chen, Qiuyue; He, Suhua; Rong, Xia; Xiao, Fei; Chen, Jun; Chen, Shoudeng (March 2021). "Structural insight reveals SARS-CoV-2 ORF7a as an immunomodulating factor for human CD14+ monocytes". iScience. 24 (3): 102187. Bibcode:2021iSci...24j2187Z. doi:10.1016/j.isci.2021.102187. PMC 7879101. PMID 33615195.
  6. ^ a b Hänel K, Stangler T, Stoldt M, Willbold D (May 2006). "Solution structure of the X4 protein coded by the SARS related coronavirus reveals an immunoglobulin like fold and suggests a binding activity to integrin I domains". J. Biomed. Sci. 13 (3): 281–93. doi:10.1007/s11373-005-9043-9. PMC 7089389. PMID 16328780.
  7. ^ Satija N, Lal SK (2007). "The molecular biology of SARS coronavirus". Ann N Y Acad Sci. 1102 (1): 26–38. Bibcode:2007NYASA1102...26S. doi:10.1196/annals.1408.002. PMC 7168024. PMID 17470909.
  8. ^ Pekosz A, Schaecher SR, Diamond MS, Fremont DH, Sims AC, Baric RS (2006). "Structure, expression, and intracellular localization of the SARS-CoV accessory proteins 7a and 7b". Adv Exp Med Biol. Advances in Experimental Medicine and Biology. 581: 115–20. doi:10.1007/978-0-387-33012-9_20. ISBN 978-0-387-26202-4. PMC 7123408. PMID 17037516.
  9. ^ Cao, Zengguo; Xia, Hongjie; Rajsbaum, Ricardo; Xia, Xianzhu; Wang, Hualei; Shi, Pei-Yong (March 2021). "Ubiquitination of SARS-CoV-2 ORF7a promotes antagonism of interferon response". Cellular & Molecular Immunology. 18 (3): 746–748. doi:10.1038/s41423-020-00603-6. PMC 7815971. PMID 33473190.
  10. ^ Pekosz, Andrew; Schaecher, Scott R.; Diamond, Michael S.; Fremont, Daved H.; Sims, Amy C.; Baric, Ralph S. (2006). "Structure, Expression, and Intracellular Localization of the SARS-CoV Accessory Proteins 7a and 7b". The Nidoviruses. Advances in Experimental Medicine and Biology. 581: 115–120. doi:10.1007/978-0-387-33012-9_20. ISBN 978-0-387-26202-4. PMC 7123408. PMID 17037516.
  11. ^ Zhang, Jing; Cruz-cosme, Ruth; Zhuang, Meng-Wei; Liu, Dongxiao; Liu, Yuan; Teng, Shaolei; Wang, Pei-Hui; Tang, Qiyi (December 2020). "A systemic and molecular study of subcellular localization of SARS-CoV-2 proteins". Signal Transduction and Targeted Therapy. 5 (1): 269. doi:10.1038/s41392-020-00372-8. PMC 7670843. PMID 33203855.
  12. ^ Flower, Thomas G.; Buffalo, Cosmo Z.; Hooy, Richard M.; Allaire, Marc; Ren, Xuefeng; Hurley, James H. (12 January 2021). "Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein". Proceedings of the National Academy of Sciences. 118 (2): e2021785118. doi:10.1073/pnas.2021785118. PMC 7812859. PMID 33361333.
  13. ^ Mariano, Giuseppina; Farthing, Rebecca J.; Lale-Farjat, Shamar L. M.; Bergeron, Julien R. C. (17 December 2020). "Structural Characterization of SARS-CoV-2: Where We Are, and Where We Need to Be". Frontiers in Molecular Biosciences. 7: 605236. doi:10.3389/fmolb.2020.605236. PMC 7773825. PMID 33392262.
  14. ^ a b Neches, Russell Y.; Kyrpides, Nikos C.; Ouzounis, Christos A. (23 February 2021). "Atypical Divergence of SARS-CoV-2 Orf8 from Orf7a within the Coronavirus Lineage Suggests Potential Stealthy Viral Strategies in Immune Evasion". mBio. 12 (1). doi:10.1128/mBio.03014-20. PMC 7845636. PMID 33468697.
  15. ^ Pereira, Filipe (November 2020). "Evolutionary dynamics of the SARS-CoV-2 ORF8 accessory gene". Infection, Genetics and Evolution. 85: 104525. doi:10.1016/j.meegid.2020.104525. PMC 7467077. PMID 32890763.
  16. ^ a b Tan, Yongjun; Schneider, Theresa; Leong, Matthew; Aravind, L.; Zhang, Dapeng (30 June 2020). "Novel Immunoglobulin Domain Proteins Provide Insights into Evolution and Pathogenesis of SARS-CoV-2-Related Viruses". mBio. 11 (3). doi:10.1128/mBio.00760-20. PMC 7267882. PMID 32471829.
  17. ^ Holland, LaRinda A.; Kaelin, Emily A.; Maqsood, Rabia; Estifanos, Bereket; Wu, Lily I.; Varsani, Arvind; Halden, Rolf U.; Hogue, Brenda G.; Scotch, Matthew; Lim, Efrem S. (July 2020). "An 81-Nucleotide Deletion in SARS-CoV-2 ORF7a Identified from Sentinel Surveillance in Arizona (January to March 2020)". Journal of Virology. 94 (14): e00711-20. doi:10.1128/JVI.00711-20. PMC 7343219. PMID 32357959.
  18. ^ Nemudryi, Artem; Nemudraia, Anna; Wiegand, Tanner; Nichols, Joseph; Snyder, Deann T.; Hedges, Jodi F.; Cicha, Calvin; Lee, Helen; Vanderwood, Karl K.; Bimczok, Diane; Jutila, Mark A.; Wiedenheft, Blake (June 2021). "SARS-CoV-2 genomic surveillance identifies naturally occurring truncation of ORF7a that limits immune suppression". Cell Reports. 35 (9): 109197. doi:10.1016/j.celrep.2021.109197. PMC 8118641. PMID 34043946.
  19. ^ Addetia, Amin; Xie, Hong; Roychoudhury, Pavitra; Shrestha, Lasata; Loprieno, Michelle; Huang, Meei-Li; Jerome, Keith R.; Greninger, Alexander L. (August 2020). "Identification of multiple large deletions in ORF7a resulting in in-frame gene fusions in clinical SARS-CoV-2 isolates". Journal of Clinical Virology. 129: 104523. doi:10.1016/j.jcv.2020.104523. PMC 7309833. PMID 32623351.
This article incorporates text from the public domain Pfam and InterPro: IPR014888

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