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Replicase polyprotein 1a (pp1a) (ORF1a polyprotein) [Cleaved into: Non-structural protein 1 (nsp1) (p9); Non-structural protein 2 (nsp2) (p87); Non-structural protein 3 (nsp3) (EC 3.4.19.12) (EC 3.4.22.-) (PL1-PRO/PL2-PRO) (PLP1/PLP2) (Papain-like proteinases 1/2) (p195); Non-structural protein 4 (nsp4) (Peptide HD2); 3C-like proteinase (3CL-PRO) (3CLp) (EC 3.4.22.-) (M-PRO) (nsp5) (p34); Non-structural protein 6 (nsp6); Non-structural protein 7 (nsp7) (p5); Non-structural protein 8 (nsp8) (p23); Non-structural protein 9 (nsp9) (p12); Non-structural protein 10 (nsp10) (Growth factor-like peptide) (GFL) (p14); Non-structural protein 11 (nsp11)]

 R1A_CVPPU               Reviewed;        4017 AA.
P0C6V2; Q9IW06;
10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
10-JUN-2008, sequence version 1.
03-JUL-2019, entry version 74.
RecName: Full=Replicase polyprotein 1a;
Short=pp1a;
AltName: Full=ORF1a polyprotein;
Contains:
RecName: Full=Non-structural protein 1;
Short=nsp1;
AltName: Full=p9;
Contains:
RecName: Full=Non-structural protein 2;
Short=nsp2;
AltName: Full=p87;
Contains:
RecName: Full=Non-structural protein 3;
Short=nsp3;
EC=3.4.19.12;
EC=3.4.22.-;
AltName: Full=PL1-PRO/PL2-PRO;
AltName: Full=PLP1/PLP2;
AltName: Full=Papain-like proteinases 1/2;
AltName: Full=p195;
Contains:
RecName: Full=Non-structural protein 4;
Short=nsp4;
AltName: Full=Peptide HD2;
Contains:
RecName: Full=3C-like proteinase;
Short=3CL-PRO;
Short=3CLp;
EC=3.4.22.-;
AltName: Full=M-PRO;
AltName: Full=nsp5;
AltName: Full=p34;
Contains:
RecName: Full=Non-structural protein 6;
Short=nsp6;
Contains:
RecName: Full=Non-structural protein 7;
Short=nsp7;
AltName: Full=p5;
Contains:
RecName: Full=Non-structural protein 8;
Short=nsp8;
AltName: Full=p23;
Contains:
RecName: Full=Non-structural protein 9;
Short=nsp9;
AltName: Full=p12;
Contains:
RecName: Full=Non-structural protein 10;
Short=nsp10;
AltName: Full=Growth factor-like peptide;
Short=GFL;
AltName: Full=p14;
Contains:
RecName: Full=Non-structural protein 11;
Short=nsp11;
ORFNames=1a;
Porcine transmissible gastroenteritis coronavirus (strain Purdue)
(TGEV).
Viruses; Riboviria; Nidovirales; Cornidovirineae; Coronaviridae;
Orthocoronavirinae; Alphacoronavirus; Tegacovirus.
NCBI_TaxID=11151;
NCBI_TaxID=9823; Sus scrofa (Pig).
[1]
NUCLEOTIDE SEQUENCE [MRNA].
STRAIN=Isolate Purdue-115;
PubMed=7856095; DOI=10.1006/viro.1995.1004;
Eleouet J., Rasschaert D., Lambert P., Levy L., Vende P., Laude H.;
"Complete sequence (20 kilobases) of the polyprotein-encoding gene 1
of transmissible gastroenteritis virus.";
Virology 206:817-822(1995).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC RNA].
STRAIN=Isolate PUR46-MAD;
PubMed=10805807; DOI=10.1073/pnas.97.10.5516;
Almazan F., Gonzalez J.M., Penzes Z., Izeta A., Calvo E.,
Plana-Duran J., Enjuanes L.;
"Engineering the largest RNA virus genome as an infectious bacterial
artificial chromosome.";
Proc. Natl. Acad. Sci. U.S.A. 97:5516-5521(2000).
[3]
PROTEOLYTIC PROCESSING OF POLYPROTEIN.
STRAIN=Isolate Purdue-115;
PubMed=11842254;
Hegyi A., Ziebuhr J.;
"Conservation of substrate specificities among coronavirus main
proteases.";
J. Gen. Virol. 83:595-599(2002).
[4]
X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 2879-3180.
PubMed=12093723; DOI=10.1093/emboj/cdf327;
Anand K., Palm G.J., Mesters J.R., Siddell S.G., Ziebuhr J.,
Hilgenfeld R.;
"Structure of coronavirus main proteinase reveals combination of a
chymotrypsin fold with an extra alpha-helical domain.";
EMBO J. 21:3213-3224(2002).
[5]
X-RAY CRYSTALLOGRAPHY (2.37 ANGSTROMS) OF 2879-3180 COMPLEXED WITH THE
SUBSTRATE-ANALOG HEXAPEPTIDYL CMK.
PubMed=12746549; DOI=10.1126/science.1085658;
Anand K., Ziebuhr J., Wadhwani P., Mesters J.R., Hilgenfeld R.;
"Coronavirus main proteinase (3CLpro) structure: basis for design of
anti-SARS drugs.";
Science 300:1763-1767(2003).
-!- FUNCTION: The papain-like proteinase 1 (PLP1) and papain-like
proteinase 2 (PLP2) are responsible for the cleavages located at
the N-terminus of the replicase polyprotein. In addition, PLP2
possesses a deubiquitinating/deISGylating activity and processes
both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from
cellular substrates. PLP2 also antagonizes innate immune induction
of type I interferon by blocking the nuclear translocation of host
IRF-3 (By similarity). {ECO:0000250}.
-!- FUNCTION: The main proteinase 3CL-PRO is responsible for the
majority of cleavages as it cleaves the C-terminus of replicase
polyprotein at 11 sites. Recognizes substrates containing the core
sequence [ILMVF]-Q-|-[SAGC]. Inhibited by the substrate-analog
Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK.
-!- FUNCTION: Nsp7-nsp8 hexadecamer may possibly confer processivity
to the polymerase, maybe by binding to dsRNA or by producing
primers utilized by the latter. {ECO:0000250}.
-!- FUNCTION: Nsp9 is a ssRNA-binding protein. {ECO:0000250}.
-!- CATALYTIC ACTIVITY:
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;
-!- SUBUNIT: 3CL-PRO exists as monomer and homodimer. Eight copies of
nsp7 and eight copies of nsp8 assemble to form a
heterohexadecamer. Nsp9 is a dimer. Nsp10 forms a dodecamer (By
similarity). {ECO:0000250}.
-!- SUBCELLULAR LOCATION: Non-structural protein 3: Host membrane
{ECO:0000305}; Multi-pass membrane protein {ECO:0000305}.
-!- SUBCELLULAR LOCATION: Non-structural protein 4: Host membrane
{ECO:0000305}; Multi-pass membrane protein {ECO:0000305}.
-!- SUBCELLULAR LOCATION: Non-structural protein 6: Host membrane
{ECO:0000305}; Multi-pass membrane protein {ECO:0000305}.
-!- SUBCELLULAR LOCATION: Non-structural protein 7: Host cytoplasm,
host perinuclear region {ECO:0000250}. Note=nsp7, nsp8, nsp9 and
nsp10 are localized in cytoplasmic foci, largely perinuclear. Late
in infection, they merge into confluent complexes (By similarity).
{ECO:0000250}.
-!- SUBCELLULAR LOCATION: Non-structural protein 8: Host cytoplasm,
host perinuclear region {ECO:0000250}. Note=nsp7, nsp8, nsp9 and
nsp10 are localized in cytoplasmic foci, largely perinuclear. Late
in infection, they merge into confluent complexes (By similarity).
{ECO:0000250}.
-!- SUBCELLULAR LOCATION: Non-structural protein 9: Host cytoplasm,
host perinuclear region {ECO:0000250}. Note=nsp7, nsp8, nsp9 and
nsp10 are localized in cytoplasmic foci, largely perinuclear. Late
in infection, they merge into confluent complexes (By similarity).
{ECO:0000250}.
-!- SUBCELLULAR LOCATION: Non-structural protein 10: Host cytoplasm,
host perinuclear region {ECO:0000250}. Note=nsp7, nsp8, nsp9 and
nsp10 are localized in cytoplasmic foci, largely perinuclear. Late
in infection, they merge into confluent complexes (By similarity).
{ECO:0000250}.
-!- ALTERNATIVE PRODUCTS:
Event=Ribosomal frameshifting; Named isoforms=2;
Name=Replicase polyprotein 1a; Synonyms=pp1a, ORF1a polyprotein;
IsoId=P0C6V2-1; Sequence=Displayed;
Note=Produced by conventional translation.;
Name=Replicase polyprotein 1ab; Synonyms=pp1ab;
IsoId=P0C6Y5-1; Sequence=External;
Note=Produced by -1 ribosomal frameshifting at the 1a-1b genes
boundary.;
-!- 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 is autocatalytically processed.
{ECO:0000269|PubMed:11842254}.
-!- SIMILARITY: Belongs to the coronaviruses polyprotein 1ab family.
{ECO:0000305}.
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EMBL; Z34093; CAA83979.1; -; mRNA.
EMBL; AJ271965; CAB91144.1; -; Genomic_RNA.
PDB; 1LVO; X-ray; 1.96 A; A/B/C/D/E/F=2879-3180.
PDB; 1P9U; X-ray; 2.37 A; A/B/C/D/E/F=2879-3180.
PDB; 2AMP; X-ray; 2.70 A; A/B=2879-3180.
PDB; 3MP2; X-ray; 2.50 A; A=1071-1281.
PDB; 3ZBD; X-ray; 1.49 A; A/B=1-105.
PDB; 4F49; X-ray; 2.25 A; A/B/C/D=2879-3181.
PDBsum; 1LVO; -.
PDBsum; 1P9U; -.
PDBsum; 2AMP; -.
PDBsum; 3MP2; -.
PDBsum; 3ZBD; -.
PDBsum; 4F49; -.
SMR; P0C6V2; -.
BRENDA; 3.4.22.B14; 4985.
EvolutionaryTrace; P0C6V2; -.
Proteomes; UP000001440; Genome.
GO; GO:0033644; C:host cell membrane; IEA:UniProtKB-SubCell.
GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
GO; GO:0004197; F:cysteine-type endopeptidase activity; IEA:InterPro.
GO; GO:0008242; F:omega peptidase activity; IEA:InterPro.
GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IEA:InterPro.
GO; GO:0036459; F:thiol-dependent ubiquitinyl hydrolase activity; IEA:UniProtKB-EC.
GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW.
GO; GO:0039648; P:modulation by virus of host protein ubiquitination; IEA:UniProtKB-KW.
GO; GO:0039548; P:suppression by virus of host IRF3 activity; IEA:UniProtKB-KW.
GO; GO:0019079; P:viral genome replication; IEA:InterPro.
GO; GO:0019082; P:viral protein processing; IEA:InterPro.
Gene3D; 1.10.150.420; -; 1.
Gene3D; 1.10.8.370; -; 1.
Gene3D; 2.30.30.1000; -; 1.
Gene3D; 2.40.10.250; -; 1.
Gene3D; 2.40.10.290; -; 1.
InterPro; IPR032039; A-CoV_nsp1.
InterPro; IPR038634; A-CoV_nsp1_sf.
InterPro; IPR032505; Corona_NSP4_C.
InterPro; IPR002589; Macro_dom.
InterPro; IPR036333; NSP10_sf.
InterPro; IPR038123; NSP4_C_sf.
InterPro; IPR014828; NSP7.
InterPro; IPR037204; NSP7_sf.
InterPro; IPR014829; NSP8.
InterPro; IPR037230; NSP8_sf.
InterPro; IPR014822; NSP9.
InterPro; IPR036499; NSP9_sf.
InterPro; IPR008740; Peptidase_C30.
InterPro; IPR013016; Peptidase_C30/C16.
InterPro; IPR009003; Peptidase_S1_PA.
InterPro; IPR018995; RNA_synth_NSP10_coronavirus.
InterPro; IPR014827; Viral_protease.
Pfam; PF16688; CNV-Replicase_N; 1.
Pfam; PF16348; Corona_NSP4_C; 1.
Pfam; PF01661; Macro; 1.
Pfam; PF09401; NSP10; 1.
Pfam; PF08716; nsp7; 1.
Pfam; PF08717; nsp8; 1.
Pfam; PF08710; nsp9; 1.
Pfam; PF05409; Peptidase_C30; 1.
Pfam; PF08715; Viral_protease; 2.
SMART; SM00506; A1pp; 1.
SUPFAM; SSF101816; SSF101816; 1.
SUPFAM; SSF140367; SSF140367; 1.
SUPFAM; SSF143076; SSF143076; 1.
SUPFAM; SSF144246; SSF144246; 2.
SUPFAM; SSF50494; SSF50494; 1.
PROSITE; PS51442; M_PRO; 1.
PROSITE; PS51154; MACRO; 1.
PROSITE; PS51124; PEPTIDASE_C16; 2.
1: Evidence at protein level;
3D-structure; Activation of host autophagy by virus;
Complete proteome; Host cytoplasm; Host membrane;
Host-virus interaction; Hydrolase;
Inhibition of host innate immune response by virus;
Inhibition of host IRF3 by virus;
Inhibition of host RLR pathway by virus; Membrane; Metal-binding;
Modulation of host ubiquitin pathway by viral deubiquitinase;
Modulation of host ubiquitin pathway by virus; Protease;
Reference proteome; Repeat; Ribosomal frameshifting; RNA-binding;
Thiol protease; Transmembrane; Transmembrane helix;
Ubl conjugation pathway; Viral immunoevasion; Zinc; Zinc-finger.
CHAIN 1 4017 Replicase polyprotein 1a.
/FTId=PRO_0000338302.
CHAIN 1 110 Non-structural protein 1. {ECO:0000250}.
/FTId=PRO_0000338303.
CHAIN 111 879 Non-structural protein 2. {ECO:0000250}.
/FTId=PRO_0000338304.
CHAIN 880 2388 Non-structural protein 3. {ECO:0000250}.
/FTId=PRO_0000338305.
CHAIN 2389 2878 Non-structural protein 4. {ECO:0000250}.
/FTId=PRO_0000338306.
CHAIN 2879 3180 3C-like proteinase.
/FTId=PRO_0000338307.
CHAIN 3181 3474 Non-structural protein 6. {ECO:0000250}.
/FTId=PRO_0000338308.
CHAIN 3475 3557 Non-structural protein 7. {ECO:0000250}.
/FTId=PRO_0000338309.
CHAIN 3558 3752 Non-structural protein 8. {ECO:0000250}.
/FTId=PRO_0000338310.
CHAIN 3753 3863 Non-structural protein 9.
/FTId=PRO_0000338311.
CHAIN 3864 3998 Non-structural protein 10. {ECO:0000250}.
/FTId=PRO_0000338312.
CHAIN 3999 4017 Non-structural protein 11. {ECO:0000255}.
/FTId=PRO_0000338313.
TRANSMEM 1896 1916 Helical. {ECO:0000255}.
TRANSMEM 1995 2015 Helical. {ECO:0000255}.
TRANSMEM 2033 2053 Helical. {ECO:0000255}.
TRANSMEM 2401 2421 Helical. {ECO:0000255}.
TRANSMEM 2467 2487 Helical. {ECO:0000255}.
TRANSMEM 2497 2517 Helical. {ECO:0000255}.
TRANSMEM 2538 2558 Helical. {ECO:0000255}.
TRANSMEM 2666 2686 Helical. {ECO:0000255}.
TRANSMEM 2695 2715 Helical. {ECO:0000255}.
TRANSMEM 2721 2741 Helical. {ECO:0000255}.
TRANSMEM 2746 2766 Helical. {ECO:0000255}.
TRANSMEM 3187 3207 Helical. {ECO:0000255}.
TRANSMEM 3217 3237 Helical. {ECO:0000255}.
TRANSMEM 3242 3262 Helical. {ECO:0000255}.
TRANSMEM 3280 3300 Helical. {ECO:0000255}.
TRANSMEM 3313 3333 Helical. {ECO:0000255}.
TRANSMEM 3347 3367 Helical. {ECO:0000255}.
TRANSMEM 3371 3391 Helical. {ECO:0000255}.
TRANSMEM 3394 3414 Helical. {ECO:0000255}.
DOMAIN 1055 1299 Peptidase C16 1. {ECO:0000255|PROSITE-
ProRule:PRU00444}.
DOMAIN 1318 1489 Macro. {ECO:0000255|PROSITE-
ProRule:PRU00490}.
DOMAIN 1550 1803 Peptidase C16 2. {ECO:0000255|PROSITE-
ProRule:PRU00444}.
DOMAIN 2879 3180 Peptidase C30. {ECO:0000255|PROSITE-
ProRule:PRU00772}.
ZN_FING 1164 1195 C4-type. {ECO:0000255|PROSITE-
ProRule:PRU00444}.
ZN_FING 3937 3953 {ECO:0000250}.
ZN_FING 3979 3992 {ECO:0000250}.
REGION 1896 2053 HD1.
REGION 2401 2766 HD2.
REGION 3187 3414 HD3.
COMPBIAS 932 1042 Glu-rich.
ACT_SITE 1093 1093 For PL1-PRO activity.
{ECO:0000255|PROSITE-ProRule:PRU00444}.
ACT_SITE 1244 1244 For PL1-PRO activity.
{ECO:0000255|PROSITE-ProRule:PRU00444}.
ACT_SITE 1588 1588 For PL2-PRO activity.
{ECO:0000255|PROSITE-ProRule:PRU00444}.
ACT_SITE 1741 1741 For PL2-PRO activity.
{ECO:0000255|PROSITE-ProRule:PRU00444}.
ACT_SITE 2919 2919 For 3CL-PRO activity.
{ECO:0000255|PROSITE-ProRule:PRU00772}.
ACT_SITE 3022 3022 For 3CL-PRO activity.
{ECO:0000255|PROSITE-ProRule:PRU00772}.
SITE 110 111 Cleavage; by PL1-PRO. {ECO:0000250}.
SITE 879 880 Cleavage; by PL1-PRO. {ECO:0000250}.
SITE 2388 2389 Cleavage; by PL2-PRO. {ECO:0000250}.
SITE 2878 2879 Cleavage; by 3CL-PRO. {ECO:0000250}.
SITE 3180 3181 Cleavage; by 3CL-PRO. {ECO:0000250}.
SITE 3474 3475 Cleavage; by 3CL-PRO. {ECO:0000250}.
SITE 3557 3558 Cleavage; by 3CL-PRO. {ECO:0000250}.
SITE 3752 3753 Cleavage; by 3CL-PRO. {ECO:0000250}.
SITE 3863 3864 Cleavage; by 3CL-PRO. {ECO:0000250}.
SITE 3998 3999 Cleavage; by 3CL-PRO. {ECO:0000250}.
VARIANT 572 572 F -> S (in strain: Isolate Purdue-115).
VARIANT 1041 1041 E -> D (in strain: Isolate Purdue-115).
VARIANT 2375 2375 P -> T (in strain: Isolate Purdue-115).
VARIANT 2381 2381 E -> Q (in strain: Isolate Purdue-115).
STRAND 4 10 {ECO:0000244|PDB: