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Details on Person UniProt:P0DTC1 pp1a
| Class:Id | ReferenceGeneProduct:9681696 |
|---|---|
| _chainChangeLog | chain:1-4405 for 9681696 added on Fri May 15 2020;chain:1-180 for 9681696 added on Fri May 15 2020;chain:181-818 for 9681696 added on Fri May 15 2020;chain:819-2763 for 9681696 added on Fri May 15 2020;chain:2764-3263 for 9681696 added on Fri May 15 2020;chain:3264-3569 for 9681696 added on Fri May 15 2020;chain:3570-3859 for 9681696 added on Fri May 15 2020;chain:3860-3942 for 9681696 added on Fri May 15 2020;chain:3943-4140 for 9681696 added on Fri May 15 2020;chain:4141-4253 for 9681696 added on Fri May 15 2020;chain:4254-4392 for 9681696 added on Fri May 15 2020;chain:4393-4405 for 9681696 added on Fri May 15 2020 |
| _displayName | UniProt:P0DTC1 pp1a |
| _timestamp | 2026-02-20 21:52:59 |
| chain | chain:1-4405 chain:1-180 chain:181-818 chain:819-2763 chain:2764-3263 chain:3264-3569 chain:3570-3859 chain:3860-3942 chain:3943-4140 chain:4141-4253 chain:4254-4392 chain:4393-4405 |
| checksum | 7F8A21148A7A7E2A |
| comment | FUNCTION Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.FUNCTION Inhibits host translation by associating with the open head conformation of the 40S subunit (PubMed:32680882, PubMed:32908316, PubMed:33080218, PubMed:33479166). The C-terminus binds to and obstructs ribosomal mRNA entry tunnel (PubMed:32680882, PubMed:32908316, PubMed:33080218, PubMed:33479166). Thereby inhibits antiviral response triggered by innate immunity or interferons (PubMed:32680882, PubMed:32979938, PubMed:33080218). The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation (By similarity). This inhibits the integrated stress response (ISR) in the infected cell by preventing EIF2S1/eIF2-alpha phosphorylation upstream of stress granule formation and depletes host G3BP1 (PubMed:36534661). Viral mRNAs less susceptible to nsp1-mediated inhibition of translation, because of their 5'-end leader sequence (PubMed:32908316, PubMed:33080218).FUNCTION Enhances mRNA repression of the 4EHP-GYF2 complex in the host, thereby inhibiting the antiviral response and facilitating SARS-CoV-2 replication. Possibly acts in cooperation with nsp1, which induces ribosome stalling on host mRNA, triggering mRNA repression by the host 4EHP-GYF2 complex which is enhanced by nsp2.FUNCTION Responsible for the cleavages located at the N-terminus of the replicase polyprotein. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication (PubMed:35551511). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:32733001). Also prevents host NF-kappa-B signaling (By similarity). In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates (PubMed:32726803). Cleaves preferentially ISG15 from antiviral protein IFIH1 (MDA5), but not RIGI (PubMed:33727702). Can play a role in host ADP-ribosylation by ADP-ribose (PubMed:32578982). Plays a role in the formation and maintenance of double membrane vesicles (DMVs) replication organelles (PubMed:35551511). DMVs are formed by nsp3 and nsp4, while nsp6 zippers ER membranes and connects to lipid droplets (PubMed:35551511).FUNCTION Plays a role in the formation and maintenance of double membrane vesicles (DMVs) replication organelles (PubMed:35551511). DMVs are formed by nsp3 and nsp4, while nsp6 zippers ER membranes and connects to lipid droplets (PubMed:35551511).FUNCTION Cleaves the C-terminus of replicase polyprotein at 11 sites (PubMed:32321856). Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN] (PubMed:32198291, PubMed:32272481). Cleaves and inactivates human TRMT1, preventing tRNA guanine(26)-dimethylation of tRNAs (PubMed:37073102, PubMed:38814682, PubMed:39773525). May cleave human NLRP1 in lung epithelial cells, thereby activating the NLRP1 inflammasome pathway (PubMed:35594856). May cleave human GSDMD, triggering alternative GSDME-mediated epithelial cell death upon activation of the NLRP1 inflammasome, which may enhance the release interleukins 1B, 6, 16 and 18 (PubMed:35594856). Also able to bind an ADP-ribose-1''-phosphate (ADRP) (PubMed:32198291, PubMed:32272481).FUNCTION Plays a role in the formation and maintenance of double membrane vesicles (DMVs) replication organelles (PubMed:35551511). DMVs are formed by nsp3 and nsp4, while nsp6 zippers ER membranes and connects to lipid droplets (LDs) (PubMed:35551511). LDs are consumed during DMV formation (PubMed:35551511). Binds to host TBK1 without affecting TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938).FUNCTION Plays a role in viral RNA synthesis (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). 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 (By similarity).FUNCTION Plays a role in viral RNA synthesis (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). 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 (By similarity). Interacts with ribosome signal recognition particle RNA (SRP) (PubMed:33080218). Together with NSP9, suppress protein integration into the cell membrane, thereby disrupting host immune defenses (PubMed:33080218).FUNCTION Catalytic subunit of viral RNA capping enzyme which catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs (PubMed:35944563). The kinase-like NiRAN domain of NSP12 transfers RNA to the amino terminus of NSP9, forming a covalent RNA-protein intermediate (PubMed:35944563). Subsequently, the NiRAN domain transfers RNA to GDP, forming the core cap structure GpppA-RNA (PubMed:35944563). The NSP14 and NSP16 methyltransferases then add methyl groups to form functional cap structures (PubMed:35944563). Interacts with ribosome signal recognition particle RNA (SRP) (PubMed:33080218). Together with NSP8, suppress protein integration into the cell membrane, thereby disrupting host immune defenses (PubMed:33080218).FUNCTION Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease (By similarity) and nsp16 2'-O-methyltransferase activities (PubMed:35944563). Therefore plays an essential role in viral mRNAs cap methylation.CATALYTIC ACTIVITY Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).CATALYTIC ACTIVITY TSAVLQ-|-SGFRK-NH2 and SGVTFQ-|-GKFKK the two peptides corresponding to the two self-cleavage sites of the SARS 3C-like proteinase are the two most reactive peptide substrates. The enzyme exhibits a strong preference for substrates containing Gln at P1 position and Leu at P2 position.CATALYTIC ACTIVITY a 5'-end diphospho-ribonucleoside in mRNA + GTP + H(+) = a 5'-end (5'-triphosphoguanosine)-ribonucleoside in mRNA + diphosphateACTIVITY REGULATION Inhibited ex vivo by K22. It may shift NSP6 zippering activity towards the nuclear envelope, thereby impairing formation of the NSP6-compartment necessary for viral transcription/replication.ACTIVITY REGULATION Inhibited in vitro by GRL-0617.ACTIVITY REGULATION Inhibited by pyridone-containing alpha-ketoamides compounds 13a and 13b. In turn, alpha-ketoamide 13b (tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate) inhibits SARS-CoV-2 replication in human lung cells (PubMed:32198291). Inhibited ex vivo by michael acceptor inhibitor N3 (PubMed:32272481). Inhibited ex vivo by compound 11a and 11b (PubMed:32321856).SUBUNIT Interacts with host PHB and PHB2.SUBUNIT May form homohexamers (PubMed:32763915). Interacts with N protein (PubMed:35044811).SUBUNIT 3CL-PRO exists as monomer and homodimer. Only the homodimer shows catalytic activity (PubMed:32198291). Interacts with host FBXO22; this interaction promotes the proteasomal degradation of nsp5 (PubMed:39223933).SUBUNIT Interacts with PL-PRO and nsp6.SUBUNIT Forms homodimers (PubMed:35551511). Interacts with host ZFYVE1 (DFCP1) (PubMed:35551511), which leads to ER and DMVs binding to lipid droplets. Interacts with host TBK1; this interaction decreases IRF3 phosphorylation by 57%, which leads to reduced IFN-beta production.SUBUNIT Interacts with nsp8 and nsp12 to form the replication-transcription complex (RTC): nsp12, nsp7, two subunits of nsp8, and up to two subunits of nsp13 (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208, PubMed:34562452). Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity).SUBUNIT Interacts with nsp7, nsp13 and nsp12 (PubMed:33232691) to form the replication-transcription complex (RTC): nsp12, nsp7, two subunits of nsp8, and up to two subunits of nsp13 (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208, PubMed:34562452). Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity).SUBUNIT Is a dimer (By similarity). Interacts with NSP12 (PubMed:35944563).SUBUNIT Forms a dodecamer and interacts with nsp14 and nsp16; these interactions enhance nsp14 and nsp16 enzymatic activities.INTERACTION Localizes in virally-induced cytoplasmic double-membrane vesicles (DMV).SUBCELLULAR LOCATION Localizes in virally-induced cytoplasmic double-membrane vesicles (DMV).SUBCELLULAR LOCATION Localizes at zppered ER membranes close to double-membrane vesicles (DMV).SUBCELLULAR LOCATION nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes.SUBCELLULAR LOCATION nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes.SUBCELLULAR LOCATION nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes.SUBCELLULAR LOCATION nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes.ALTERNATIVE PRODUCTS Normal translation results in Replicase polyprotein 1a. Ribosomal frameshifting at the end of this protein occurs at low frequency and produces Replicase polyprotein 1ab.DOMAIN The hydrophobic domains (HD) could mediate the membrane association of the replication complex and thereby alter the architecture of the host cell membrane.PTM Specific enzymatic cleavages in vivo by its own proteases yield mature proteins. 3CL-PRO and PL-PRO proteinases are autocatalytically processed.POLYMORPHISM Variant B.1.1.7 is also called Variant Of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, or 20B/501Y.V1.POLYMORPHISM Variant Omicron/BA.1 and BA.2 belong to a lineage first isolated in South Africa (November 2021).POLYMORPHISM Variant Omicron/BQ.1.1 belongs to a lineage first isolated in Nigeria (November 2022).POLYMORPHISM Variant Omicron/XBB.1.5 belongs to a lineage first isolated in United States (November 2022). It is the result of recombination between omicron BJ.1 and BM.1.1. Moreover XBB.1.5 do not express ORF8.MISCELLANEOUS Produced by conventional translation.SIMILARITY Belongs to the coronaviruses polyprotein 1ab family. |
| created | [InstanceEdit:9681685] D'Eustachio, Peter, 2020-04-03 |
| description | recommendedName: Replicase polyprotein 1a shortName: pp1a alternativeName: ORF1a polyprotein component recommendedName: Host translation inhibitor nsp1 alternativeName: Leader protein alternativeName: Non-structural protein 1 shortName: nsp1 /component component recommendedName: Non-structural protein 2 shortName: nsp2 alternativeName: p65 homolog /component component recommendedName: fullName evidence="57"Papain-like protease nsp3 ecNumber evidence="36"3.4.19.12 ecNumber: 3.4.22.- alternativeName: Non-structural protein 3 shortName: nsp3 alternativeName: PL2-PRO alternativeName: Papain-like proteinase shortName: PL-PRO /component component recommendedName: Non-structural protein 4 shortName: nsp4 /component component recommendedName: 3C-like proteinase nsp5 shortName: 3CL-PRO shortName: 3CLp ecNumber: 3.4.22.69 alternativeName: Main protease shortName evidence="56"Mpro alternativeName: Non-structural protein 5 shortName: nsp5 alternativeName: SARS coronavirus main proteinase /component component recommendedName: Non-structural protein 6 shortName: nsp6 /component component recommendedName: Non-structural protein 7 shortName: nsp7 /component component recommendedName: Non-structural protein 8 shortName: nsp8 /component component recommendedName: RNA-capping enzyme subunit nsp9 alternativeName: Non-structural protein 9 shortName: nsp9 ecNumber evidence="50"2.7.7.50 /component component recommendedName: Non-structural protein 10 shortName: nsp10 alternativeName: Growth factor-like peptide shortName: GFL /component component recommendedName: Non-structural protein 11 shortName: nsp11 /component |
| geneName | pp1a |
| identifier | P0DTC1 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Activation of host autophagy by virus Decay of host mRNAs by virus Disulfide bond Endonuclease Eukaryotic host gene expression shutoff by virus Eukaryotic host translation shutoff by virus Host cytoplasm Host endoplasmic reticulum Host endosome Host gene expression shutoff by virus Host Golgi apparatus Host membrane Host mRNA suppression by virus Host nucleus Host-virus interaction Hydrolase Inhibition of host innate immune response by virus Inhibition of host interferon signaling pathway by virus Inhibition of host IRF3 by virus Inhibition of host ISG15 by virus Inhibition of host RLR pathway by virus Interferon antiviral system evasion Isopeptide bond Membrane Metal-binding Methyltransferase Modulation of host ubiquitin pathway by viral deubiquitinase Modulation of host ubiquitin pathway by virus Nuclease Protease Reference proteome Repeat Ribosomal frameshifting RNA-binding Thiol protease Transferase Transmembrane Transmembrane helix Ubl conjugation Ubl conjugation pathway Viral immunoevasion Zinc Zinc-finger |
| modified | [InstanceEdit:9688885] Weiser, JD [InstanceEdit:9698430] Weiser, JD [InstanceEdit:9706439] Weiser, JD [InstanceEdit:9715482] Weiser, JD [InstanceEdit:9730071] Weiser, JD [InstanceEdit:9750299] Weiser, JD [InstanceEdit:9767224] Weiser, Joel [InstanceEdit:9773244] Weiser, Joel [InstanceEdit:9796772] Weiser, Joel [InstanceEdit:9829221] Weiser, Joel [InstanceEdit:9834092] Weiser, Joel [InstanceEdit:9841277] Weiser, Joel [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9909836] Weiser, Joel, 2024-05-14 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21 [InstanceEdit:9963647] Weiser, Joel, 2025-08-15 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | Replicase polyprotein 1a |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| secondaryIdentifier | R1A_SARS2 |
| sequenceLength | 4405 |
| species | [Species:9681683] Severe acute respiratory syndrome coronavirus 2 |
| (isoformParent) | [ReferenceIsoform:9689017] UniProt:P0DTC1-1 Unknown [Severe acute respiratory syndrome coronavirus 2] |
| (referenceEntity) | [EntityWithAccessionedSequence:9681983] pp1a-nsp10 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681984] pp1a-nsp4 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681986] pp1a [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681988] pp1a-nsp2 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681989] pp1a-nsp1 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681990] pp1a-nsp11 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681991] pp1a-nsp9 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681992] pp1a-nsp8 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681993] pp1a-nsp3 [cytosol] [Severe acute respiratory syndrome coronavirus 2] [EntityWithAccessionedSequence:9681994] pp1a-3CL [cytosol] [Severe acute respiratory syndrome coronavirus 2] |
| (referenceSequence) | [ModifiedResidue:9684338] N-glycosylated residue at 2871 [ModifiedResidue:9694442] N-glycosylated residue at unknown position [ModifiedResidue:9765954] N6-(phospho-5'-guanosine)-L-lysine at 3861 |
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No pathways have been reviewed or authored by UniProt:P0DTC1 pp1a (9681696)
