| Structural highlights
Function
R1AB_SARS Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response (PubMed:23035226). May disrupt nuclear pore function by binding and displacing host NUP93 (PubMed:30943371).[1] [2] May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[3] Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates (PubMed:17692280). Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:19369340, PubMed:24622840). Prevents also host NF-kappa-B signaling.[4] [5] [6] [7] [8] Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Alone appears incapable to induce membrane curvature, but together with nsp3 is able to induce paired membranes. Nsp3, nsp4 and nsp6 together are sufficient to form DMV.[9] [10] Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Also able to bind an ADP-ribose-1-phosphate (ADRP). May cleave host ATP6V1G1 thereby modifying host vacuoles intracellular pH.[PROSITE-ProRule:PRU00772][11] Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes (PubMed:24991833).[12] [13] Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[14] Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[15] May participate in viral replication by acting as a ssRNA-binding protein.[16] Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[17] Responsible for replication and transcription of the viral RNA genome.[18] Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[19] [20] Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity (PubMed:16549795, PubMed:20421945, PubMed:22635272). Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens (PubMed:23966862, PubMed:29511076, PubMed:21593585).[21] [22] [23] [24] [25] [26] Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond. Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[27] [28]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the three-dimensional structures of several of the replicase/transcriptase components of SARS coronavirus (SARS-CoV), the non-structural proteins (Nsps), have been determined. However, within the large Nsp3 (1922 amino-acid residues), the structure and function of the so-called SARS-unique domain (SUD) have remained elusive. SUD occurs only in SARS-CoV and the highly related viruses found in certain bats, but is absent from all other coronaviruses. Therefore, it has been speculated that it may be involved in the extreme pathogenicity of SARS-CoV, compared to other coronaviruses, most of which cause only mild infections in humans. In order to help elucidate the function of the SUD, we have determined crystal structures of fragment 389-652 ("SUD(core)") of Nsp3, which comprises 264 of the 338 residues of the domain. Both the monoclinic and triclinic crystal forms (2.2 and 2.8 A resolution, respectively) revealed that SUD(core) forms a homodimer. Each monomer consists of two subdomains, SUD-N and SUD-M, with a macrodomain fold similar to the SARS-CoV X-domain. However, in contrast to the latter, SUD fails to bind ADP-ribose, as determined by zone-interference gel electrophoresis. Instead, the entire SUD(core) as well as its individual subdomains interact with oligonucleotides known to form G-quadruplexes. This includes oligodeoxy- as well as oligoribonucleotides. Mutations of selected lysine residues on the surface of the SUD-N subdomain lead to reduction of G-quadruplex binding, whereas mutations in the SUD-M subdomain abolish it. As there is no evidence for Nsp3 entering the nucleus of the host cell, the SARS-CoV genomic RNA or host-cell mRNA containing long G-stretches may be targets of SUD. The SARS-CoV genome is devoid of G-stretches longer than 5-6 nucleotides, but more extended G-stretches are found in the 3'-nontranslated regions of mRNAs coding for certain host-cell proteins involved in apoptosis or signal transduction, and have been shown to bind to SUD in vitro. Therefore, SUD may be involved in controlling the host cell's response to the viral infection. Possible interference with poly(ADP-ribose) polymerase-like domains is also discussed.
The SARS-unique domain (SUD) of SARS coronavirus contains two macrodomains that bind G-quadruplexes.,Tan J, Vonrhein C, Smart OS, Bricogne G, Bollati M, Kusov Y, Hansen G, Mesters JR, Schmidt CL, Hilgenfeld R PLoS Pathog. 2009 May;5(5):e1000428. Epub 2009 May 15. PMID:19436709[29]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lokugamage KG, Narayanan K, Huang C, Makino S. Severe acute respiratory syndrome coronavirus protein nsp1 is a novel eukaryotic translation inhibitor that represses multiple steps of translation initiation. J Virol. 2012 Dec;86(24):13598-608. doi: 10.1128/JVI.01958-12. Epub 2012 Oct 3. PMID:23035226 doi:http://dx.doi.org/10.1128/JVI.01958-12
- ↑ Gomez GN, Abrar F, Dodhia MP, Gonzalez FG, Nag A. SARS coronavirus protein nsp1 disrupts localization of Nup93 from the nuclear pore complex. Biochem Cell Biol. 2019 Dec;97(6):758-766. doi: 10.1139/bcb-2018-0394. Epub 2019 , Apr 3. PMID:30943371 doi:http://dx.doi.org/10.1139/bcb-2018-0394
- ↑ Cornillez-Ty CT, Liao L, Yates JR 3rd, Kuhn P, Buchmeier MJ. Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling. J Virol. 2009 Oct;83(19):10314-8. Epub 2009 Jul 29. PMID:19640993 doi:http://dx.doi.org/JVI.00842-09
- ↑ Saikatendu KS, Joseph JS, Subramanian V, Clayton T, Griffith M, Moy K, Velasquez J, Neuman BW, Buchmeier MJ, Stevens RC, Kuhn P. Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1-phosphate dephosphorylation by a conserved domain of nsP3. Structure. 2005 Nov;13(11):1665-75. PMID:16271890 doi:10.1016/j.str.2005.07.022
- ↑ Lindner HA, Lytvyn V, Qi H, Lachance P, Ziomek E, Menard R. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys. 2007 Oct 1;466(1):8-14. Epub 2007 Jul 14. PMID:17692280 doi:10.1016/j.abb.2007.07.006
- ↑ Frieman M, Ratia K, Johnston RE, Mesecar AD, Baric RS. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol. 2009 Jul;83(13):6689-705. doi: 10.1128/JVI.02220-08. Epub 2009 Apr 15. PMID:19369340 doi:10.1128/JVI.02220-08
- ↑ Chen X, Yang X, Zheng Y, Yang Y, Xing Y, Chen Z. SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex. Protein Cell. 2014 May;5(5):369-81. doi: 10.1007/s13238-014-0026-3. Epub 2014 Mar, 14. PMID:24622840 doi:http://dx.doi.org/10.1007/s13238-014-0026-3
- ↑ Angelini MM, Neuman BW, Buchmeier MJ. Untangling membrane rearrangement in the nidovirales. DNA Cell Biol. 2014 Mar;33(3):122-7. doi: 10.1089/dna.2013.2304. Epub 2014 Jan, 10. PMID:24410069 doi:http://dx.doi.org/10.1089/dna.2013.2304
- ↑ Angelini MM, Akhlaghpour M, Neuman BW, Buchmeier MJ. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. mBio. 2013 Aug 13;4(4). pii: mBio.00524-13. doi: 10.1128/mBio.00524-13. PMID:23943763 doi:http://dx.doi.org/10.1128/mBio.00524-13
- ↑ Angelini MM, Neuman BW, Buchmeier MJ. Untangling membrane rearrangement in the nidovirales. DNA Cell Biol. 2014 Mar;33(3):122-7. doi: 10.1089/dna.2013.2304. Epub 2014 Jan, 10. PMID:24410069 doi:http://dx.doi.org/10.1089/dna.2013.2304
- ↑ Lin CW, Tsai FJ, Wan L, Lai CC, Lin KH, Hsieh TH, Shiu SY, Li JY. Binding interaction of SARS coronavirus 3CL(pro) protease with vacuolar-H+ ATPase G1 subunit. FEBS Lett. 2005 Nov 7;579(27):6089-94. doi: 10.1016/j.febslet.2005.09.075. Epub, 2005 Oct 6. PMID:16226257 doi:http://dx.doi.org/10.1016/j.febslet.2005.09.075
- ↑ Cottam EM, Whelband MC, Wileman T. Coronavirus NSP6 restricts autophagosome expansion. Autophagy. 2014 Aug;10(8):1426-41. doi: 10.4161/auto.29309. Epub 2014 Jun 11. PMID:24991833 doi:http://dx.doi.org/10.4161/auto.29309
- ↑ Angelini MM, Neuman BW, Buchmeier MJ. Untangling membrane rearrangement in the nidovirales. DNA Cell Biol. 2014 Mar;33(3):122-7. doi: 10.1089/dna.2013.2304. Epub 2014 Jan, 10. PMID:24410069 doi:http://dx.doi.org/10.1089/dna.2013.2304
- ↑ te Velthuis AJ, van den Worm SH, Snijder EJ. The SARS-coronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension. Nucleic Acids Res. 2012 Feb;40(4):1737-47. doi: 10.1093/nar/gkr893. Epub 2011 Oct, 29. PMID:22039154 doi:http://dx.doi.org/10.1093/nar/gkr893
- ↑ te Velthuis AJ, van den Worm SH, Snijder EJ. The SARS-coronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension. Nucleic Acids Res. 2012 Feb;40(4):1737-47. doi: 10.1093/nar/gkr893. Epub 2011 Oct, 29. PMID:22039154 doi:http://dx.doi.org/10.1093/nar/gkr893
- ↑ Miknis ZJ, Donaldson EF, Umland TC, Rimmer RA, Baric RS, Schultz LW. Severe acute respiratory syndrome coronavirus nsp9 dimerization is essential for efficient viral growth. J Virol. 2009 Apr;83(7):3007-18. Epub 2009 Jan 19. PMID:19153232 doi:10.1128/JVI.01505-08
- ↑ Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E. RNA 3'-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9372-7. doi:, 10.1073/pnas.1201130109. Epub 2012 May 25. PMID:22635272 doi:http://dx.doi.org/10.1073/pnas.1201130109
- ↑ Ahn DG, Choi JK, Taylor DR, Oh JW. Biochemical characterization of a recombinant SARS coronavirus nsp12 RNA-dependent RNA polymerase capable of copying viral RNA templates. Arch Virol. 2012 Nov;157(11):2095-104. doi: 10.1007/s00705-012-1404-x. Epub 2012 , Jul 13. PMID:22791111 doi:http://dx.doi.org/10.1007/s00705-012-1404-x
- ↑ Tanner JA, Watt RM, Chai YB, Lu LY, Lin MC, Peiris JS, Poon LL, Kung HF, Huang JD. The severe acute respiratory syndrome (SARS) coronavirus NTPase/helicase belongs to a distinct class of 5' to 3' viral helicases. J Biol Chem. 2003 Oct 10;278(41):39578-82. Epub 2003 Aug 13. PMID:12917423 doi:http://dx.doi.org/10.1074/jbc.C300328200
- ↑ Adedeji AO, Marchand B, Te Velthuis AJ, Snijder EJ, Weiss S, Eoff RL, Singh K, Sarafianos SG. Mechanism of nucleic acid unwinding by SARS-CoV helicase. PLoS One. 2012;7(5):e36521. doi: 10.1371/journal.pone.0036521. Epub 2012 May 15. PMID:22615777 doi:http://dx.doi.org/10.1371/journal.pone.0036521
- ↑ Minskaia E, Hertzig T, Gorbalenya AE, Campanacci V, Cambillau C, Canard B, Ziebuhr J. Discovery of an RNA virus 3'->5' exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5108-13. Epub 2006 Mar 20. PMID:16549795 doi:http://dx.doi.org/0508200103
- ↑ Bouvet M, Debarnot C, Imbert I, Selisko B, Snijder EJ, Canard B, Decroly E. In vitro reconstitution of SARS-coronavirus mRNA cap methylation. PLoS Pathog. 2010 Apr 22;6(4):e1000863. doi: 10.1371/journal.ppat.1000863. PMID:20421945 doi:http://dx.doi.org/10.1371/journal.ppat.1000863
- ↑ Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS. Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol. 2011 Mar-Apr;8(2):270-9. doi: 10.4161/rna.8.2.15013. Epub 2011 Mar 1. PMID:21593585 doi:http://dx.doi.org/10.4161/rna.8.2.15013
- ↑ Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E. RNA 3'-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9372-7. doi:, 10.1073/pnas.1201130109. Epub 2012 May 25. PMID:22635272 doi:http://dx.doi.org/10.1073/pnas.1201130109
- ↑ Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog. 2013 Aug;9(8):e1003565. doi: 10.1371/journal.ppat.1003565. Epub 2013, Aug 15. PMID:23966862 doi:http://dx.doi.org/10.1371/journal.ppat.1003565
- ↑ Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. doi: 10.1128/mBio.00221-18. PMID:29511076 doi:http://dx.doi.org/10.1128/mBio.00221-18
- ↑ Decroly E, Imbert I, Coutard B, Bouvet M, Selisko B, Alvarez K, Gorbalenya AE, Snijder EJ, Canard B. Coronavirus nonstructural protein 16 is a cap-0 binding enzyme possessing (nucleoside-2'O)-methyltransferase activity. J Virol. 2008 Aug;82(16):8071-84. doi: 10.1128/JVI.00407-08. Epub 2008 Apr 16. PMID:18417574 doi:http://dx.doi.org/10.1128/JVI.00407-08
- ↑ Bouvet M, Debarnot C, Imbert I, Selisko B, Snijder EJ, Canard B, Decroly E. In vitro reconstitution of SARS-coronavirus mRNA cap methylation. PLoS Pathog. 2010 Apr 22;6(4):e1000863. doi: 10.1371/journal.ppat.1000863. PMID:20421945 doi:http://dx.doi.org/10.1371/journal.ppat.1000863
- ↑ Tan J, Vonrhein C, Smart OS, Bricogne G, Bollati M, Kusov Y, Hansen G, Mesters JR, Schmidt CL, Hilgenfeld R. The SARS-unique domain (SUD) of SARS coronavirus contains two macrodomains that bind G-quadruplexes. PLoS Pathog. 2009 May;5(5):e1000428. Epub 2009 May 15. PMID:19436709 doi:10.1371/journal.ppat.1000428
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