SARS-CoV-2 protein ORF7a

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The genome of SARS-CoV-2 codes for an ORF1a/ ORF1ab (open reading frame) polyprotein containing sixteen non-structural proteins (NSP) and four structural proteins. Additionally, the genome comprises a variable number of open reading frames coding for accessory proteins. These accessory proteins (3a,b; 6; 7a,b; 8; 9b,c; 10) are not necessary for virus replication but might play a key role in pathogenesis [1].

Overall Structure

The SARS-CoV-2 accessory protein 7a has high sequence similarity with one in SARS-CoV. In SARS-CoV, sequence analysis predicts that ORF7a codes for a type I transmembrane protein with 122 amino acids including a signal peptide at the N-terminus and a retrieval signal at the C-terminus [2]. The N-terminal ectodomain of ORF7a (SARS-CoV) consists of seven β-strands, compactly arranged in an immunoglobulin-like β-sandwich fold. These seven β-strands are arranged in two β-sheets containing four β-strands (A; G; F; C) in the first sheet and three (B; E; D) in the second one. Both sheets are amphipathic and with the hydrophobic side inwards closely packed against each other. The top of the ectodomain is defined by the BC, DE and FG loops and the bottom by the AB, CD and EF loops. The β-sandwich structure is stabilized by two disulphide bonds linking the sheets at opposite edges. At the bottom of the structure, a disulphide bridge connects a Cys8 of strand A with Cys43 at the end of strand E. At the top, Cys20 of the BC loop is linked to Cys54 at the end of strand F. Additional on top of the BED sheet , the DE loop protrudes from the structure and forms a groove together with the β-strands C and D. In the centre is a Glu18 which contributes to a negatively charged bottom of the mainly hydrophobic groove. This groove may be a potential site for ligand interaction due to its central negative electrostatic potential [3].

Fuction

In cell culture, the polypeptide 7a of SARS-CoV with 85% sequence identity and 95.2% sequence similarity to SARS-CoV-2, seems to have diverse biological functions [4] [5]. SARS-CoV 7a is predicted to induce apoptosis in human kidney epithelial cells by interaction with Bcl-XL. Bcl-XL belongs to a group of pro-survival proteins, the BCL-2 family, which prevent apoptosis in epithelial cells. The Interaction between SARS-7a and the C-terminal transmembrane domain of Bcl-XL may interfere with this pro-survival function, leading to apoptosis via the caspase-dependant pathway [6] [7]. Additionally, interaction of SARS 7a with Ap4A, a hydrolase involved in processes such as cell proliferation, DNA-replication, apoptosis and RNA-processing, leads to downregulation of its hydrolase-activity followed by an increased production of AP4A, which may also contributes to the induction of apoptosis [8]. It is also possible that 7a plays a key role in cell cycle control. In HEK 293 cell, an overexpression of 7a led to inhibition of cell growth and induction of the G0/G1 phase cell cycle arrest. This arrest may favour coronavirus replication and exacerbate virus-induced pathogenicity [9].


See also

Coronavirus_Disease 2019 (COVID-19)
SARS-CoV-2_virus_proteins
COVID-19 AlphaFold2 Models


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Accessory Protein 7a from SARS-CoV2 (PDB entry 6w37)

References

  1. ↑ Michel, Christian Jean; Mayer, Claudine; Poch, Olivier; Thompson, Julie Dawn (2020): Characterization of accessory genes in coronavirus genomes. In: Virol J 17 (1), S. 131. DOI: 10.1186/s12985-020-01402-1
  2. ↑ Fielding, Burtram C.; Tan, Yee-Joo; Shuo, Shen; Tan, Timothy H. P.; Ooi, Eng-Eong; Lim, Seng Gee et al. (2004): Characterization of a unique group-specific protein (U122) of the severe acute respiratory syndrome coronavirus. In: Journal of Virology 78 (14), S. 7311–7318. DOI: 10.1128/JVI.78.14.7311-7318.2004.
  3. ↑ Hänel, Karen; Stangler, Thomas; Stoldt, Matthias; Willbold, Dieter (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. In: Journal of biomedical science 13 (3), S. 281–293. DOI: 10.1007/s11373-005-9043-9
  4. ↑ Vasilenko, Natalia; Moshynskyy, Igor; Zakhartchouk, Alexander (2010): SARS coronavirus protein 7a interacts with human Ap4A-hydrolase. In: Virol J 7, S. 31. DOI: 10.1186/1743-422X-7-31.
  5. ↑ Francis K. Yoshimoto (2020): The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. In: Protein J 39 (3), S. 198–216. DOI: 10.1007/s10930-020-09901-4.
  6. ↑ Tan, Yee-Joo; Fielding, Burtram C.; Goh, Phuay-Yee; Shen, Shuo; Tan, Timothy H. P.; Lim, Seng Gee; Hong, Wanjin (2004): Overexpression of 7a, a protein specifically encoded by the severe acute respiratory syndrome coronavirus, induces apoptosis via a caspase-dependent pathway. In: Journal of Virology 78 (24), S. 14043–14047. DOI: 10.1128/JVI.78.24.14043-14047.2004.
  7. ↑ Tan, Ying-Xim; Tan, Timothy H. P.; Lee, Marvin J-R; Tham, Puay-Yoke; Gunalan, Vithiagaran; Druce, Julian et al. (2007): Induction of apoptosis by the severe acute respiratory syndrome coronavirus 7a protein is dependent on its interaction with the Bcl-XL protein. In: Journal of Virology 81 (12), S. 6346–6355. DOI: 10.1128/JVI.00090-07.
  8. ↑ Vasilenko, Natalia; Moshynskyy, Igor; Zakhartchouk, Alexander (2010): SARS coronavirus protein 7a interacts with human Ap4A-hydrolase. In: Virol J 7, S. 31. DOI: 10.1186/1743-422X-7-31.
  9. ↑ Yuan, Xiaoling; Wu, Jie; Shan, Yajun; Yao, Zhenyu; Dong, Bo; Chen, Bo et al. (2006): SARS coronavirus 7a protein blocks cell cycle progression at G0/G1 phase via the cyclin D3/pRb pathway. In: Virology 346 (1), S. 74–85. DOI: 10.1016/j.virol.2005.10.015.

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