| Structural highlights
Function
R1A_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]
Publication Abstract from PubMed
The Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)) cleaves two virion polyproteins (pp1a and pp1ab); this essential process represents an attractive target for the development of anti-SARS drugs. The functional unit of M(pro) is a homodimer and each subunit contains a His41/Cys145 catalytic dyad. Large amounts of biochemical and structural information are available on M(pro); nevertheless, the mechanism by which monomeric M(pro) is converted into a dimer during maturation still remains poorly understood. Previous studies have suggested that a C-terminal residue, Arg298, interacts with Ser123 of the other monomer in the dimer, and mutation of Arg298 results in a monomeric structure with a collapsed substrate-binding pocket. Interestingly, the R298A mutant of M(pro) shows a reversible substrate-induced dimerization that is essential for catalysis. Here, the conformational change that occurs during substrate-induced dimerization is delineated by X-ray crystallography. A dimer with a mutual orientation of the monomers that differs from that of the wild-type protease is present in the asymmetric unit. The presence of a complete substrate-binding pocket and oxyanion hole in both protomers suggests that they are both catalytically active, while the two domain IIIs show minor reorganization. This structural information offers valuable insights into the molecular mechanism associated with substrate-induced dimerization and has important implications with respect to the maturation of the enzyme.
Mechanism for controlling the monomer-dimer conversion of SARS coronavirus main protease.,Wu CG, Cheng SC, Chen SC, Li JY, Fang YH, Chen YH, Chou CY Acta Crystallogr D Biol Crystallogr. 2013 May;69(Pt 5):747-55. doi:, 10.1107/S0907444913001315. Epub 2013 Apr 11. PMID:23633583[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Wu CG, Cheng SC, Chen SC, Li JY, Fang YH, Chen YH, Chou CY. Mechanism for controlling the monomer-dimer conversion of SARS coronavirus main protease. Acta Crystallogr D Biol Crystallogr. 2013 May;69(Pt 5):747-55. doi:, 10.1107/S0907444913001315. Epub 2013 Apr 11. PMID:23633583 doi:10.1107/S0907444913001315
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