UniProt functional annotation for P0DTD1



	UniProt functional annotation for P0DTD1

UniProt code: P0DTD1.

Organism: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2).

Taxonomy: Viruses; Riboviria; Orthornavirae; Pisuviricota; Pisoniviricetes; Nidovirales; Cornidovirineae; Coronaviridae; Orthocoronavirinae; Betacoronavirus; Sarbecovirus.

Function: [Replicase polyprotein 1ab]: Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. {ECO:0000250|UniProtKB:P0C6X7}.

Function: [Host translation inhibitor nsp1]: Inhibits host translation by interacting with binds to the host 40S subunit in ribosomal complexes, including the 43S pre-initiation complex and the non- translating 80S ribosome (PubMed:32680882,PubMed:32908316). The C- terminus binds to and obstructs ribosomal mRNA entry tunnel (PubMed:32680882,PubMed:32908316). Thereby inhibits antiviral response triggered by innate immunity or interferons (PubMed:32680882,PubMed:32979938). The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation (By similarity). Viral mRNAs less susceptible to nsp1-mediated inhibition of translation, because of their 5'-end leader sequence (PubMed:32908316). By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response (By similarity). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32680882, ECO:0000269|PubMed:32908316, ECO:0000269|PubMed:32979938}.

Function: [Non-structural protein 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. {ECO:0000250|UniProtKB:P0C6X7}.

Function: [Non-structural protein 3]: 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 (By similarity). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:32733001). Prevents also 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 substrates in vitro (PubMed:32726803). Can play a role in host ADP-ribosylation by binding ADP-ribose (PubMed:32578982). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32578982, ECO:0000269|PubMed:32726803, ECO:0000269|PubMed:32733001}.

Function: [Non-structural protein 4]: Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. {ECO:0000250|UniProtKB:P0C6X7}.

Function: [3C-like proteinase]: 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). Also able to bind an ADP-ribose-1''-phosphate (ADRP) (By similarity) (PubMed:32198291, PubMed:32272481). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32198291, ECO:0000269|PubMed:32272481, ECO:0000269|PubMed:32321856}.

Function: [Non-structural protein 6]: Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic (By similarity). Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes (By similarity). Binds to host TBK1 without affecting TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32979938}.

Function: [Non-structural protein 7]: Plays a role in viral RNA synthesis (PubMed:32358203, PubMed:32277040, 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). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203, ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.

Function: [Non-structural protein 8]: Plays a role in viral RNA synthesis (PubMed:32358203, PubMed:32277040, 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). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203, ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.

Function: [Non-structural protein 9]: May participate in viral replication by acting as a ssRNA-binding protein. {ECO:0000250|UniProtKB:P0C6X7}.

Function: [Non-structural protein 10]: 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. {ECO:0000250|UniProtKB:P0C6X7}.

Function: [RNA-directed RNA polymerase]: Responsible for replication and transcription of the viral RNA genome. {ECO:0000305|PubMed:32277040, ECO:0000305|PubMed:32358203, ECO:0000305|PubMed:32438371, ECO:0000305|PubMed:32526208}.

Function: [Helicase]: 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 (By similarity). Binds to host TBK1 and inhibits TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32979938}.

Function: [Proofreading exoribonuclease]: 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. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens. {ECO:0000250|UniProtKB:P0C6X7}.

Function: [Uridylate-specific endoribonuclease]: Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond. {ECO:0000250|UniProtKB:P0C6X7}.

Function: [2'-O-methyltransferase]: 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. {ECO:0000250|UniProtKB:P0C6X7}.

Catalytic activity: [RNA-directed RNA polymerase]: Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate + RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:11128, Rhea:RHEA- COMP:11129, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:83400; EC=2.7.7.48; Evidence={ECO:0000269|PubMed:32358203, ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208};

Catalytic activity: [Helicase]: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12; Evidence={ECO:0000250|UniProtKB:P0C6X7};

Catalytic activity: [Helicase]: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13; Evidence={ECO:0000250|UniProtKB:P0C6X7};

Catalytic activity: [3C-like proteinase]: Reaction=TSAVLQ-|-SGFRK-NH(2) 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.; EC=3.4.22.69; Evidence={ECO:0000269|PubMed:32198291, ECO:0000269|PubMed:32272481, ECO:0000269|PubMed:32321856};

Catalytic activity: [Non-structural protein 3]: Reaction=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).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:32726803};

Activity regulation: [Non-structural protein 3]: Inhibited in vitro by GRL-0617. {ECO:0000269|PubMed:32726803}.

Activity regulation: [Proofreading exoribonuclease]: Inhibited by Remdesivir antiviral drug (GS-5734). {ECO:0000250|UniProtKB:P0C6X7}.

Activity regulation: [RNA-directed RNA polymerase]: Inhibited by Remdesivir antiviral drug (GS-5734) through non-obligate RNA chain termination. {ECO:0000269|PubMed:32358203, ECO:0000269|PubMed:32526208}.

Activity regulation: [3C-like proteinase]: 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). {ECO:0000269|PubMed:32198291, ECO:0000269|PubMed:32272481, ECO:0000269|PubMed:32321856}.

Subunit: [Non-structural protein 2]: Interacts with host PHB and PHB2. {ECO:0000250|UniProtKB:P0C6X7}.

Subunit: [3C-like proteinase]: 3CL-PRO exists as monomer and homodimer. Only the homodimer shows catalytic activity. {ECO:0000269|PubMed:32198291}.

Subunit: [Non-structural protein 4]: Interacts with PL-PRO and nsp6. {ECO:0000250|UniProtKB:P0C6X7}.

Subunit: [Non-structural protein 6]: Interacts with host TBK1; this interaction decreases by 57% IRF3 phosphorylation, which leads to reduced IFN-beta production. {ECO:0000269|PubMed:32979938}.

Subunit: [Non-structural protein 7]: Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity). Interacts with RNA-directed RNA polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203, ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.

Subunit: [Non-structural protein 8]: Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity). Interacts with RNA-directed RNA polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203, ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.

Subunit: [Non-structural protein 9]: Is a dimer. {ECO:0000250|UniProtKB:P0C6X7}.

Subunit: [Non-structural protein 10]: Forms a dodecamer and interacts with nsp14 and nsp16; these interactions enhance nsp14 and nsp16 enzymatic activities. {ECO:0000250|UniProtKB:P0C6X7}.

Subunit: [RNA-directed RNA polymerase]: Interacts with nsp7 and nsp8. {ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203, ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.

Subunit: [Helicase]: Interacts with host TBK1; this interaction inhibits TBK1 phosphorylation and decreases by 75% IRF3 phosphorylation, which leads to reduced IFN-beta production. {ECO:0000269|PubMed:32979938}.

Subunit: [Proofreading exoribonuclease]: Interacts (via N-terminus) with DDX1. Interacts with nsp10. {ECO:0000250|UniProtKB:P0C6X7}.

Subunit: [2'-O-methyltransferase]: Interacts with nsp10. {ECO:0000250|UniProtKB:P0C6X7}.

Subcellular location: [Host translation inhibitor nsp1]: Host cytoplasm {ECO:0000269|PubMed:33060197}.

Subcellular location: [Non-structural protein 2]: Host cytoplasm {ECO:0000269|PubMed:33060197}. Host endosome {ECO:0000269|PubMed:33060197}.

Subcellular location: [Non-structural protein 3]: Host membrane {ECO:0000250|UniProtKB:P0C6X7}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P0C6X7}. Host cytoplasm {ECO:0000250|UniProtKB:P0C6X7}.

Subcellular location: [Non-structural protein 4]: Host membrane {ECO:0000250|UniProtKB:P0C6X7}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P0C6X7}. Host cytoplasm {ECO:0000250|UniProtKB:P0C6X7}. Note=Localizes in virally-induced cytoplasmic double-membrane vesicles. {ECO:0000250|UniProtKB:P0C6X7}.

Subcellular location: [3C-like proteinase]: Host cytoplasm {ECO:0000269|PubMed:33060197}. Host Golgi apparatus {ECO:0000269|PubMed:33060197}.

Subcellular location: [Non-structural protein 6]: Host membrane {ECO:0000250|UniProtKB:P0C6X7}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P0C6X7}.

Subcellular location: [Non-structural protein 7]: Host cytoplasm, host perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.

Subcellular location: [Non-structural protein 8]: Host cytoplasm, host perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.

Subcellular location: [Non-structural protein 9]: Host cytoplasm, host perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.

Subcellular location: [Non-structural protein 10]: Host cytoplasm, host perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.

Subcellular location: [Proofreading exoribonuclease]: Host cytoplasm {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum.

Subcellular location: [Helicase]: Host endoplasmic reticulum-Golgi intermediate compartment {ECO:0000250|UniProtKB:P0C6X7}. Note=The helicase interacts with the N protein in membranous complexes and colocalizes with sites of synthesis of new viral RNA. {ECO:0000250|UniProtKB:P0C6X9}.

Subcellular location: [Uridylate-specific endoribonuclease]: Host cytoplasm, host perinuclear region {ECO:0000250|UniProtKB:P0C6X9}.

Domain: The hydrophobic domains (HD) could mediate the membrane association of the replication complex and thereby alter the architecture of the host cell membrane. {ECO:0000250|UniProtKB:P0C6X7}.

Ptm: Specific enzymatic cleavages in vivo by its own proteases yield mature proteins. 3CL-PRO and PL-PRO proteinases are autocatalytically processed. {ECO:0000250|UniProtKB:P0C6X7}.

Miscellaneous: [Replicase polyprotein 1ab]: Produced by -1 ribosomal frameshifting at the 1a-1b genes boundary. {ECO:0000250|UniProtKB:P0C6X7}.

Miscellaneous: Variant B.1.1.7 is also called Variant Of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, or 20B/501Y.V1. {ECO:0000305|PubMed:33413740}.

Similarity: Belongs to the coronaviruses polyprotein 1ab family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2).
Taxonomy:		Viruses; Riboviria; Orthornavirae; Pisuviricota; Pisoniviricetes; Nidovirales; Cornidovirineae; Coronaviridae; Orthocoronavirinae; Betacoronavirus; Sarbecovirus.



Function:		[Replicase polyprotein 1ab]: Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. {ECO:0000250\|UniProtKB:P0C6X7}.



Function:		[Host translation inhibitor nsp1]: Inhibits host translation by interacting with binds to the host 40S subunit in ribosomal complexes, including the 43S pre-initiation complex and the non- translating 80S ribosome (PubMed:32680882,PubMed:32908316). The C- terminus binds to and obstructs ribosomal mRNA entry tunnel (PubMed:32680882,PubMed:32908316). Thereby inhibits antiviral response triggered by innate immunity or interferons (PubMed:32680882,PubMed:32979938). The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation (By similarity). Viral mRNAs less susceptible to nsp1-mediated inhibition of translation, because of their 5'-end leader sequence (PubMed:32908316). By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response (By similarity). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32680882, ECO:0000269\|PubMed:32908316, ECO:0000269\|PubMed:32979938}.



Function:		[Non-structural protein 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. {ECO:0000250\|UniProtKB:P0C6X7}.



Function:		[Non-structural protein 3]: 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 (By similarity). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:32733001). Prevents also 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 substrates in vitro (PubMed:32726803). Can play a role in host ADP-ribosylation by binding ADP-ribose (PubMed:32578982). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32578982, ECO:0000269\|PubMed:32726803, ECO:0000269\|PubMed:32733001}.



Function:		[Non-structural protein 4]: Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. {ECO:0000250\|UniProtKB:P0C6X7}.



Function:		[3C-like proteinase]: 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). Also able to bind an ADP-ribose-1''-phosphate (ADRP) (By similarity) (PubMed:32198291, PubMed:32272481). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32198291, ECO:0000269\|PubMed:32272481, ECO:0000269\|PubMed:32321856}.



Function:		[Non-structural protein 6]: Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic (By similarity). Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes (By similarity). Binds to host TBK1 without affecting TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32979938}.



Function:		[Non-structural protein 7]: Plays a role in viral RNA synthesis (PubMed:32358203, PubMed:32277040, 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). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32277040, ECO:0000269\|PubMed:32358203, ECO:0000269\|PubMed:32438371, ECO:0000269\|PubMed:32526208}.



Function:		[Non-structural protein 8]: Plays a role in viral RNA synthesis (PubMed:32358203, PubMed:32277040, 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). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32277040, ECO:0000269\|PubMed:32358203, ECO:0000269\|PubMed:32438371, ECO:0000269\|PubMed:32526208}.



Function:		[Non-structural protein 9]: May participate in viral replication by acting as a ssRNA-binding protein. {ECO:0000250\|UniProtKB:P0C6X7}.



Function:		[Non-structural protein 10]: 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. {ECO:0000250\|UniProtKB:P0C6X7}.



Function:		[RNA-directed RNA polymerase]: Responsible for replication and transcription of the viral RNA genome. {ECO:0000305\|PubMed:32277040, ECO:0000305\|PubMed:32358203, ECO:0000305\|PubMed:32438371, ECO:0000305\|PubMed:32526208}.



Function:		[Helicase]: 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 (By similarity). Binds to host TBK1 and inhibits TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32979938}.



Function:		[Proofreading exoribonuclease]: 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. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens. {ECO:0000250\|UniProtKB:P0C6X7}.



Function:		[Uridylate-specific endoribonuclease]: Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond. {ECO:0000250\|UniProtKB:P0C6X7}.



Function:		[2'-O-methyltransferase]: 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. {ECO:0000250\|UniProtKB:P0C6X7}.


Catalytic activity:		[RNA-directed RNA polymerase]: Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate + RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:11128, Rhea:RHEA- COMP:11129, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:83400; EC=2.7.7.48; Evidence={ECO:0000269\|PubMed:32358203, ECO:0000269\|PubMed:32438371, ECO:0000269\|PubMed:32526208};
Catalytic activity:		[Helicase]: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.12; Evidence={ECO:0000250\|UniProtKB:P0C6X7};
Catalytic activity:		[Helicase]: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13; Evidence={ECO:0000250\|UniProtKB:P0C6X7};
Catalytic activity:		[3C-like proteinase]: Reaction=TSAVLQ-\|-SGFRK-NH(2) 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.; EC=3.4.22.69; Evidence={ECO:0000269\|PubMed:32198291, ECO:0000269\|PubMed:32272481, ECO:0000269\|PubMed:32321856};
Catalytic activity:		[Non-structural protein 3]: Reaction=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).; EC=3.4.19.12; Evidence={ECO:0000269\|PubMed:32726803};
Activity regulation:		[Non-structural protein 3]: Inhibited in vitro by GRL-0617. {ECO:0000269\|PubMed:32726803}.
Activity regulation:		[Proofreading exoribonuclease]: Inhibited by Remdesivir antiviral drug (GS-5734). {ECO:0000250\|UniProtKB:P0C6X7}.
Activity regulation:		[RNA-directed RNA polymerase]: Inhibited by Remdesivir antiviral drug (GS-5734) through non-obligate RNA chain termination. {ECO:0000269\|PubMed:32358203, ECO:0000269\|PubMed:32526208}.
Activity regulation:		[3C-like proteinase]: 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). {ECO:0000269\|PubMed:32198291, ECO:0000269\|PubMed:32272481, ECO:0000269\|PubMed:32321856}.
Subunit:		[Non-structural protein 2]: Interacts with host PHB and PHB2. {ECO:0000250\|UniProtKB:P0C6X7}.
Subunit:		[3C-like proteinase]: 3CL-PRO exists as monomer and homodimer. Only the homodimer shows catalytic activity. {ECO:0000269\|PubMed:32198291}.
Subunit:		[Non-structural protein 4]: Interacts with PL-PRO and nsp6. {ECO:0000250\|UniProtKB:P0C6X7}.
Subunit:		[Non-structural protein 6]: Interacts with host TBK1; this interaction decreases by 57% IRF3 phosphorylation, which leads to reduced IFN-beta production. {ECO:0000269\|PubMed:32979938}.
Subunit:		[Non-structural protein 7]: Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity). Interacts with RNA-directed RNA polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32277040, ECO:0000269\|PubMed:32358203, ECO:0000269\|PubMed:32438371, ECO:0000269\|PubMed:32526208}.
Subunit:		[Non-structural protein 8]: Eight copies of nsp7 and eight copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling ring structure (By similarity). Interacts with RNA-directed RNA polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). {ECO:0000250\|UniProtKB:P0C6X7, ECO:0000269\|PubMed:32277040, ECO:0000269\|PubMed:32358203, ECO:0000269\|PubMed:32438371, ECO:0000269\|PubMed:32526208}.
Subunit:		[Non-structural protein 9]: Is a dimer. {ECO:0000250\|UniProtKB:P0C6X7}.
Subunit:		[Non-structural protein 10]: Forms a dodecamer and interacts with nsp14 and nsp16; these interactions enhance nsp14 and nsp16 enzymatic activities. {ECO:0000250\|UniProtKB:P0C6X7}.
Subunit:		[RNA-directed RNA polymerase]: Interacts with nsp7 and nsp8. {ECO:0000269\|PubMed:32277040, ECO:0000269\|PubMed:32358203, ECO:0000269\|PubMed:32438371, ECO:0000269\|PubMed:32526208}.
Subunit:		[Helicase]: Interacts with host TBK1; this interaction inhibits TBK1 phosphorylation and decreases by 75% IRF3 phosphorylation, which leads to reduced IFN-beta production. {ECO:0000269\|PubMed:32979938}.
Subunit:		[Proofreading exoribonuclease]: Interacts (via N-terminus) with DDX1. Interacts with nsp10. {ECO:0000250\|UniProtKB:P0C6X7}.
Subunit:		[2'-O-methyltransferase]: Interacts with nsp10. {ECO:0000250\|UniProtKB:P0C6X7}.
Subcellular location:		[Host translation inhibitor nsp1]: Host cytoplasm {ECO:0000269\|PubMed:33060197}.
Subcellular location:		[Non-structural protein 2]: Host cytoplasm {ECO:0000269\|PubMed:33060197}. Host endosome {ECO:0000269\|PubMed:33060197}.
Subcellular location:		[Non-structural protein 3]: Host membrane {ECO:0000250\|UniProtKB:P0C6X7}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P0C6X7}. Host cytoplasm {ECO:0000250\|UniProtKB:P0C6X7}.
Subcellular location:		[Non-structural protein 4]: Host membrane {ECO:0000250\|UniProtKB:P0C6X7}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P0C6X7}. Host cytoplasm {ECO:0000250\|UniProtKB:P0C6X7}. Note=Localizes in virally-induced cytoplasmic double-membrane vesicles. {ECO:0000250\|UniProtKB:P0C6X7}.
Subcellular location:		[3C-like proteinase]: Host cytoplasm {ECO:0000269\|PubMed:33060197}. Host Golgi apparatus {ECO:0000269\|PubMed:33060197}.
Subcellular location:		[Non-structural protein 6]: Host membrane {ECO:0000250\|UniProtKB:P0C6X7}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P0C6X7}.
Subcellular location:		[Non-structural protein 7]: Host cytoplasm, host perinuclear region {ECO:0000250\|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269\|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269\|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250\|UniProtKB:P0C6X9}.
Subcellular location:		[Non-structural protein 8]: Host cytoplasm, host perinuclear region {ECO:0000250\|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269\|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269\|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250\|UniProtKB:P0C6X9}.
Subcellular location:		[Non-structural protein 9]: Host cytoplasm, host perinuclear region {ECO:0000250\|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269\|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269\|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250\|UniProtKB:P0C6X9}.
Subcellular location:		[Non-structural protein 10]: Host cytoplasm, host perinuclear region {ECO:0000250\|UniProtKB:P0C6X9}. Host cytoplasm {ECO:0000269\|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269\|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear. Late in infection, they merge into confluent complexes. {ECO:0000250\|UniProtKB:P0C6X9}.
Subcellular location:		[Proofreading exoribonuclease]: Host cytoplasm {ECO:0000269\|PubMed:33060197}. Host endoplasmic reticulum {ECO:0000269\|PubMed:33060197}. Host endoplasmic reticulum.
Subcellular location:		[Helicase]: Host endoplasmic reticulum-Golgi intermediate compartment {ECO:0000250\|UniProtKB:P0C6X7}. Note=The helicase interacts with the N protein in membranous complexes and colocalizes with sites of synthesis of new viral RNA. {ECO:0000250\|UniProtKB:P0C6X9}.
Subcellular location:		[Uridylate-specific endoribonuclease]: Host cytoplasm, host perinuclear region {ECO:0000250\|UniProtKB:P0C6X9}.
Domain:		The hydrophobic domains (HD) could mediate the membrane association of the replication complex and thereby alter the architecture of the host cell membrane. {ECO:0000250\|UniProtKB:P0C6X7}.
Ptm:		Specific enzymatic cleavages in vivo by its own proteases yield mature proteins. 3CL-PRO and PL-PRO proteinases are autocatalytically processed. {ECO:0000250\|UniProtKB:P0C6X7}.
Miscellaneous:		[Replicase polyprotein 1ab]: Produced by -1 ribosomal frameshifting at the 1a-1b genes boundary. {ECO:0000250\|UniProtKB:P0C6X7}.
Miscellaneous:		Variant B.1.1.7 is also called Variant Of Concern (VOC) 202012/01, Variant Under Investigation (VUI) 202012/01, or 20B/501Y.V1. {ECO:0000305\|PubMed:33413740}.
Similarity:		Belongs to the coronaviruses polyprotein 1ab family. {ECO:0000305}.