Gene found in coronaviruses of the Betacoronavirus genus
Protein family
ORF7a (also known by several other names, including SARS coronavirus X4 , SARS-X4 , ORF7a , or U122 )[ 1] 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] 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] [ 5] [ 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] 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] 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] [ 2] 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] beta sheets , arranged in a beta sandwich .[ 2] 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
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] overlapping gene that overlaps ORF7b .[ 10] subcellular localization to the endoplasmic reticulum , Golgi apparatus , and ERGIC has been reported,[ 1] [ 11]
Evolution
Structural superposition of the Ig domains of ORF8 (blue, PDB : 7JTL [ 12] PDB : 7CI3 [ 5] beta-sandwich topologies. It is thought that ORF8 paralog of ORF7a that originated through gene duplication ,[ 13] [ 14] bioinformatics analyses suggest the similarity may be too low to support duplication, which is relatively uncommon in viruses.[ 15] 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] [ 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] gene fusion .[ 19]
References
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Journal of Virology . 80 (15): 7287– 7294. doi :10.1128/JVI.00414-06 . PMC 1563709 PMID 16840309 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . ^ 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 . 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