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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) (p16); Non-structural protein 11 (nsp11)]

 R1A_CVH22               Reviewed;        4085 AA.
P0C6U2; Q05002;
10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
10-JUN-2008, sequence version 1.
03-JUL-2019, entry version 72.
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=p16;
Contains:
RecName: Full=Non-structural protein 11;
Short=nsp11;
ORFNames=1a;
Human coronavirus 229E (HCoV-229E).
Viruses; Riboviria; Nidovirales; Cornidovirineae; Coronaviridae;
Orthocoronavirinae; Alphacoronavirus; Duvinacovirus.
NCBI_TaxID=11137;
NCBI_TaxID=9606; Homo sapiens (Human).
[1]
NUCLEOTIDE SEQUENCE [GENOMIC RNA].
PubMed=11369870;
Thiel V., Herold J., Schelle B., Siddell S.G.;
"Infectious RNA transcribed in vitro from a cDNA copy of the human
coronavirus genome cloned in vaccinia virus.";
J. Gen. Virol. 82:1273-1281(2001).
[2]
NUCLEOTIDE SEQUENCE [GENOMIC RNA].
PubMed=8337838; DOI=10.1006/viro.1993.1419;
Herold J., Raabe T., Schelle-Prinz B., Siddell S.G.;
"Nucleotide sequence of the human coronavirus 229E RNA polymerase
locus.";
Virology 195:680-691(1993).
[3]
CHARACTERIZATION OF 3CL-PRO, AND MUTAGENESIS OF HIS-3006; HIS-3028;
ASN-3029; GLU-3074; THR-3099; CYS-3109; HIS-3127; HIS-3136 AND
GLN-3267.
PubMed=9094676;
Ziebuhr J., Heusipp G., Siddell S.G.;
"Biosynthesis, purification, and characterization of the human
coronavirus 229E 3C-like proteinase.";
J. Virol. 71:3992-3997(1997).
[4]
ZINC-FINGER DOMAIN OF PL1-PRO, AND MUTAGENESIS OF LYS-1048; GLY-1099;
GLY-1102; CYS-1126; CYS-1128; CYS-1154; LEU-1155; CYS-1157; CYS-1163;
VAL-1175; CYS-1203 AND ASP-1218.
PubMed=10329692; DOI=10.1074/jbc.274.21.14918;
Herold J., Siddell S.G., Gorbalenya A.E.;
"A human RNA viral cysteine proteinase that depends upon a unique
Zn2+-binding finger connecting the two domains of a papain-like
fold.";
J. Biol. Chem. 274:14918-14925(1999).
[5]
ERRATUM.
Herold J., Siddell S.G., Gorbalenya A.E.;
J. Biol. Chem. 274:21490-21490(1999).
[6]
PROTEOLYTIC PROCESSING OF POLYPROTEIN.
PubMed=9847320;
Ziebuhr J., Siddell S.G.;
"Processing of the human coronavirus 229E replicase polyproteins by
the virus-encoded 3C-like proteinase: identification of proteolytic
products and cleavage sites common to pp1a and pp1ab.";
J. Virol. 73:177-185(1999).
[7]
PROTEOLYTIC PROCESSING OF POLYPROTEIN, AND MUTAGENESIS OF CYS-1054 AND
TRP-1702.
PubMed=11431476; DOI=10.1074/jbc.M104097200;
Ziebuhr J., Thiel V., Gorbalenya A.E.;
"The autocatalytic release of a putative RNA virus transcription
factor from its polyprotein precursor involves two paralogous papain-
like proteases that cleave the same peptide bond.";
J. Biol. Chem. 276:33220-33232(2001).
[8]
PROTEOLYTIC PROCESSING OF POLYPROTEIN.
PubMed=11842254;
Hegyi A., Ziebuhr J.;
"Conservation of substrate specificities among coronavirus main
proteases.";
J. Gen. Virol. 83:595-599(2002).
[9]
MUTAGENESIS OF ASN-3029.
PubMed=11842253;
Hegyi A., Friebe A., Gorbalenya A.E., Ziebuhr J.;
"Mutational analysis of the active centre of coronavirus 3C-like
proteases.";
J. Gen. Virol. 83:581-593(2002).
[10]
X-RAY CRYSTALLOGRAPHY (2.54 ANGSTROMS) OF 2966-3265.
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-|-[SGACN]. Inhibited by the substrate-analog
Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK. Also contains an ADP-ribose-1''-
phosphate (ADRP)-binding function (By similarity).
{ECO:0000255|PROSITE-ProRule:PRU00772}.
-!- 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=P0C6U2-1; Sequence=Displayed;
Note=Produced by conventional translation.;
Name=Replicase polyprotein 1ab; Synonyms=pp1ab;
IsoId=P0C6X1-1; 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 and PL-PRO proteinases are
autocatalytically processed. {ECO:0000269|PubMed:11431476,
ECO:0000269|PubMed:11842254, ECO:0000269|PubMed:9847320}.
-!- SIMILARITY: Belongs to the coronaviruses polyprotein 1ab family.
{ECO:0000305}.
-!- WEB RESOURCE: Name=Protein Spotlight; Note=Proteic grace - Issue
77 of December 2006;
URL="https://web.expasy.org/spotlight/back_issues/077";
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EMBL; AF304460; AAG48590.1; -; Genomic_RNA.
EMBL; X69721; CAA49377.1; -; Genomic_RNA.
PIR; S28600; S28600.
RefSeq; NP_073550.1; NC_002645.1. [P0C6U2-1]
PDB; 1P9S; X-ray; 2.54 A; A/B=2966-3265.
PDB; 2ZU2; X-ray; 1.80 A; A/B=2966-3267.
PDB; 3EWQ; X-ray; 2.10 A; A=1269-1436.
PDB; 3EWR; X-ray; 2.01 A; A=1269-1436.
PDBsum; 1P9S; -.
PDBsum; 2ZU2; -.
PDBsum; 3EWQ; -.
PDBsum; 3EWR; -.
SMR; P0C6U2; -.
PRIDE; P0C6U2; -.
GeneID; 918764; -.
EvolutionaryTrace; P0C6U2; -.
Proteomes; UP000006716; 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; IPR038634; A-CoV_nsp1_sf.
InterPro; IPR023298; ATPase_P-typ_TM_dom_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; IPR011050; Pectin_lyase_fold/virulence.
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; 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; 1.
SUPFAM; SSF50494; SSF50494; 1.
SUPFAM; SSF51126; SSF51126; 1.
SUPFAM; SSF81665; SSF81665; 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 4085 Replicase polyprotein 1a.
/FTId=PRO_0000338182.
CHAIN 1 111 Non-structural protein 1.
/FTId=PRO_0000338183.
CHAIN 112 897 Non-structural protein 2.
/FTId=PRO_0000338184.
CHAIN 898 2484 Non-structural protein 3.
/FTId=PRO_0000338185.
CHAIN 2485 2965 Non-structural protein 4.
/FTId=PRO_0000338186.
CHAIN 2966 3267 3C-like proteinase.
/FTId=PRO_0000338187.
CHAIN 3268 3546 Non-structural protein 6.
/FTId=PRO_0000338188.
CHAIN 3547 3629 Non-structural protein 7.
/FTId=PRO_0000338189.
CHAIN 3630 3824 Non-structural protein 8.
/FTId=PRO_0000338190.
CHAIN 3825 3933 Non-structural protein 9.
/FTId=PRO_0000338191.
CHAIN 3934 4068 Non-structural protein 10.
/FTId=PRO_0000338192.
CHAIN 4069 4085 Non-structural protein 11. {ECO:0000255}.
/FTId=PRO_0000338193.
TRANSMEM 1998 2018 Helical. {ECO:0000255}.
TRANSMEM 2068 2088 Helical. {ECO:0000255}.
TRANSMEM 2095 2115 Helical. {ECO:0000255}.
TRANSMEM 2491 2511 Helical. {ECO:0000255}.
TRANSMEM 2731 2751 Helical. {ECO:0000255}.
TRANSMEM 2755 2775 Helical. {ECO:0000255}.
TRANSMEM 278