ORF7a

Last updated
Betacoronavirus NS7A protein
PDB 1xak EBI.jpg
Structure of the SARS-coronavirus ORF7a accessory protein
Identifiers
SymbolbCoV_NS7A
Pfam PF08779
InterPro IPR014888
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure 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]

Contents

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
SARS-CoV-2 genome.svg
Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2, indicating the location of ORF7a
NCBI genome ID 86693
Genome size 29,903 bases
Year of completion 2020
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 ) and ORF7a (orange, PDB: 7CI3 ) illustrating the similarity of their beta-sandwich topologies. 7jtl orf8 7ci3 orf7a superposition.png
Structural superposition of the Ig domains of ORF8 (blue, PDB: 7JTL ​ ) and ORF7a (orange, PDB: 7CI3 ​ ) 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]

Related Research Articles

<span class="mw-page-title-main">Coronavirus</span> Subfamily of viruses in the family Coronaviridae

Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold, while more lethal varieties can cause SARS, MERS and COVID-19, which is causing the ongoing pandemic. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis.

<span class="mw-page-title-main">SARS-related coronavirus</span> Species of coronavirus causing SARS and COVID-19

Severe acute respiratory syndrome–related coronavirus is a species of virus consisting of many known strains phylogenetically related to severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) that have been shown to possess the capability to infect humans, bats, and certain other mammals. These enveloped, positive-sense single-stranded RNA viruses enter host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. The SARSr-CoV species is a member of the genus Betacoronavirus and of the subgenus Sarbecovirus.

<i>Murine coronavirus</i> Species of virus

Murine coronavirus (M-CoV) is a virus in the genus Betacoronavirus that infects mice. Belonging to the subgenus Embecovirus, murine coronavirus strains are enterotropic or polytropic. Enterotropic strains include mouse hepatitis virus (MHV) strains D, Y, RI, and DVIM, whereas polytropic strains, such as JHM and A59, primarily cause hepatitis, enteritis, and encephalitis. Murine coronavirus is an important pathogen in the laboratory mouse and the laboratory rat. It is the most studied coronavirus in animals other than humans, and has been used as an animal disease model for many virological and clinical studies.

Putative transmembrane domain more commonly known as Non-structural Protein 6 (NSP6) is one of the two non-structural proteins that gene 11 in rotavirus encodes for alongside NSP5. NSP6 is composed of six transmembrane domains and a C terminal tail. In contrast to the other rotavirus non-structural proteins, NSP6 was found to have a high rate of turnover, being completely degraded within 2 hours of synthesis. NSP6 was found to be a sequence-independent nucleic acid binding protein, with similar affinities for ssRNA and dsRNA

<span class="mw-page-title-main">Poliovirus receptor-related 1</span> Protein-coding gene in the species Homo sapiens

Poliovirus receptor-related 1 (PVRL1), also known as nectin-1 and CD111 (formerly herpesvirus entry mediator C, HVEC) is a human protein of the immunoglobulin superfamily (IgSF), also considered a member of the nectins. It is a membrane protein with three extracellular immunoglobulin domains, a single transmembrane helix and a cytoplasmic tail. The protein can mediate Ca2+-independent cellular adhesion further characterizing it as IgSF cell adhesion molecule (IgSF CAM).

Feline coronavirus (FCoV) is a positive-stranded RNA virus that infects cats worldwide. It is a coronavirus of the species Alphacoronavirus 1, which includes canine coronavirus (CCoV) and porcine transmissible gastroenteritis coronavirus (TGEV). FCoV has two different forms: feline enteric coronavirus (FECV), which infects the intestines, and feline infectious peritonitis virus (FIPV), which causes the disease feline infectious peritonitis (FIP).

<i>Betacoronavirus</i> Genus of viruses

Betacoronavirus is one of four genera of coronaviruses. Member viruses are enveloped, positive-strand RNA viruses that infect mammals. The natural reservoir for betacoronaviruses are bats and rodents. Rodents are the reservoir for the subgenus Embecovirus, while bats are the reservoir for the other subgenera.

ORF3b is a gene found in coronaviruses of the subgenus Sarbecovirus, encoding a short non-structural protein. It is present in both SARS-CoV and SARS-CoV-2, though the protein product has very different lengths in the two viruses. The encoded protein is significantly shorter in SARS-CoV-2, at only 22 amino acid residues compared to 153–155 in SARS-CoV. Both the longer SARS-CoV and shorter SARS-CoV-2 proteins have been reported as interferon antagonists. It is unclear whether the SARS-CoV-2 gene expresses a functional protein.

ORF3d is a gene found in SARS-CoV-2 and at least one closely related coronavirus found in pangolins, though it is not found in other closely related viruses within the Sarbecovirus subgenus. It is 57 codons long and encodes a novel 57 amino acid residue protein of unknown function. At least two isoforms have been described, of which the shorter 33-residue form, ORF3d-2, may be more highly expressed, or even the only form expressed. It is reported to be antigenic and antibodies to the ORF3d protein occur in patients recovered from COVID-19. There is no homolog in the genome of the otherwise closely related SARS-CoV.

<span class="mw-page-title-main">Coronavirus envelope protein</span> Major structure in coronaviruses

The envelope (E) protein is the smallest and least well-characterized of the four major structural proteins found in coronavirus virions. It is an integral membrane protein less than 110 amino acid residues long; in SARS-CoV-2, the causative agent of Covid-19, the E protein is 75 residues long. Although it is not necessarily essential for viral replication, absence of the E protein may produce abnormally assembled viral capsids or reduced replication. E is a multifunctional protein and, in addition to its role as a structural protein in the viral capsid, it is thought to be involved in viral assembly, likely functions as a viroporin, and is involved in viral pathogenesis.

<span class="mw-page-title-main">Coronavirus membrane protein</span> Major structure in coronaviruses

The membrane (M) protein is an integral membrane protein that is the most abundant of the four major structural proteins found in coronaviruses. The M protein organizes the assembly of coronavirus virions through protein-protein interactions with other M protein molecules as well as with the other three structural proteins, the envelope (E), spike (S), and nucleocapsid (N) proteins.

<span class="mw-page-title-main">Coronavirus nucleocapsid protein</span> Most expressed structure in coronaviruses

The nucleocapsid (N) protein is a protein that packages the positive-sense RNA genome of coronaviruses to form ribonucleoprotein structures enclosed within the viral capsid. The N protein is the most highly expressed of the four major coronavirus structural proteins. In addition to its interactions with RNA, N forms protein-protein interactions with the coronavirus membrane protein (M) during the process of viral assembly. N also has additional functions in manipulating the cell cycle of the host cell. The N protein is highly immunogenic and antibodies to N are found in patients recovered from SARS and COVID-19.

<span class="mw-page-title-main">Coronavirus spike protein</span> Glycoprotein spike on a viral capsid or viral envelope

Spike (S) glycoprotein is the largest of the four major structural proteins found in coronaviruses. The spike protein assembles into trimers that form large structures, called spikes or peplomers, that project from the surface of the virion. The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona", gives the virus family its main name.

<span class="mw-page-title-main">ORF3a</span> Gene found in coronaviruses of the subgenus Sarbecovirus

ORF3a is a gene found in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It encodes an accessory protein about 275 amino acid residues long, which is thought to function as a viroporin. It is the largest accessory protein and was the first of the SARS-CoV accessory proteins to be described.

ORF7b is a gene found in coronaviruses of the genus Betacoronavirus, which expresses the accessory protein Betacoronavirus NS7b protein. It is a short, highly hydrophobic transmembrane protein of unknown function.

<span class="mw-page-title-main">ORF8</span> Gene that encodes a viral accessory protein

ORF8 is a gene that encodes a viral accessory protein, Betacoronavirus NS8 protein, in coronaviruses of the subgenus Sarbecovirus. It is one of the least well conserved and most variable parts of the genome. In some viruses, a deletion splits the region into two smaller open reading frames, called ORF8a and ORF8b - a feature present in many SARS-CoV viral isolates from later in the SARS epidemic, as well as in some bat coronaviruses. For this reason the full-length gene and its protein are sometimes called ORF8ab. The full-length gene, exemplified in SARS-CoV-2, encodes a protein with an immunoglobulin domain of unknown function, possibly involving interactions with the host immune system. It is similar in structure to the ORF7a protein, suggesting it may have originated through gene duplication.

ORF6 is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is not present in MERS-CoV. It is thought to reduce the immune system response to viral infection through interferon antagonism.

<span class="mw-page-title-main">ORF9b</span> Gene

ORF9b is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is an overlapping gene whose open reading frame is entirely contained within the N gene, which encodes coronavirus nucleocapsid protein. The encoded protein is 97 amino acid residues long in SARS-CoV and 98 in SARS-CoV-2, in both cases forming a protein dimer.

ORF1ab refers collectively to two open reading frames (ORFs), ORF1a and ORF1b, that are conserved in the genomes of nidoviruses, a group of viruses that includes coronaviruses. The genes express large polyproteins that undergo proteolysis to form several nonstructural proteins with various functions in the viral life cycle, including proteases and the components of the replicase-transcriptase complex (RTC). Together the two ORFs are sometimes referred to as the replicase gene. They are related by a programmed ribosomal frameshift that allows the ribosome to continue translating past the stop codon at the end of ORF1a, in a -1 reading frame. The resulting polyproteins are known as pp1a and pp1ab.

<span class="mw-page-title-main">Nidoviral papain-like protease</span>

The nidoviral papain-like protease is a papain-like protease protein domain encoded in the genomes of nidoviruses. It is expressed as part of a large polyprotein from the ORF1a gene and has cysteine protease enzymatic activity responsible for proteolytic cleavage of some of the N-terminal viral nonstructural proteins within the polyprotein. A second protease also encoded by ORF1a, called the 3C-like protease or main protease, is responsible for the majority of further cleavages. Coronaviruses have one or two papain-like protease domains; in SARS-CoV and SARS-CoV-2, one PLPro domain is located in coronavirus nonstructural protein 3 (nsp3). Arteriviruses have two to three PLP domains. In addition to their protease activity, PLP domains function as deubiquitinating enzymes (DUBs) that can cleave the isopeptide bond found in ubiquitin chains. They are also "deISGylating" enzymes that remove the ubiquitin-like domain interferon-stimulated gene 15 (ISG15) from cellular proteins. These activities are likely responsible for antagonizing the activity of the host innate immune system. Because they are essential for viral replication, papain-like protease domains are considered drug targets for the development of antiviral drugs against human pathogens such as MERS-CoV, SARS-CoV, and SARS-CoV-2.

References

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  2. 1 2 3 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. 1 2 3 4 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. 1 2 3 4 5 6 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. 1 2 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. 1 2 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. 1 2 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.
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