Reviewed, UniProtKB/Swiss-Prot Q05794 (POLG_HAVHA)

Names and origin

Protein names	Recommended name:     Genome polyprotein Cleaved into the following 18 chains:     1- Recommended name:             Protein VP0         Alternative name(s):             VP4-VP2     2- Recommended name:             Protein VP4         Alternative name(s):             Virion protein 4             P1A     3- Recommended name:             Protein VP2         Alternative name(s):             Virion protein 2             P1B     4- Recommended name:             Protein VP3         Alternative name(s):             Virion protein 3             P1C     5- Recommended name:             Protein VP1-2A         Alternative name(s):             PX     6- Recommended name:             Protein VP1         Alternative name(s):             Virion protein 1             P1D     7- Recommended name:             Protein 2A                 Short name=P2A     8- Recommended name:             Protein 2BC     9- Recommended name:             Protein 2B                 Short name=P2B     10- Recommended name:             Protein 2C                 Short name=P2C               EC=3.6.1.15     11- Recommended name:             Protein 3ABCD                 Short name=P3     12- Recommended name:             Protein 3ABC     13- Recommended name:             Protein 3AB     14- Recommended name:             Protein 3A                 Short name=P3A     15- Recommended name:             Protein 3B                 Short name=P3B         Alternative name(s):             VPg     16- Recommended name:             Protein 3CD     17- Recommended name:             Picornain 3C               EC=3.4.22.28         Alternative name(s):             Protease 3C               Short name=P3C     18- Recommended name:             RNA-directed RNA polymerase 3D-POL                 Short name=P3D-POL               EC=2.7.7.48
Organism	Human hepatitis A virus genotype IA (isolate HAS-15) (HHAV) (Human hepatitis A virus (isolate Human/Arizona/HAS-15/1979))
Taxonomic identifier	470424 [NCBI]
Taxonomic lineage	Viruses › ssRNA positive-strand viruses, no DNA stage › Picornavirales › Picornaviridae › Hepatovirus
Virus host	Homo sapiens (Human) [TaxID: 9606]

Protein attributes

Sequence length	2052 AA.
Sequence status	Fragments.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Inferred from homology.

General annotation (Comments)

Function	Capsid proteins VP1, VP2, and VP3 form a closed capsid enclosing the viral positive strand RNA genome. All these proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The capsid interacts with HAVCR1 to provide virion attachment to target cell By similarity. VP0 precursor is a component of immature procapsids. The N-terminal domain of VP0, protein VP4, is needed for the assembly of 12 pentamers into the icosahedral structure. Unlike other picornaviruses, HAV VP4 does not seem to be myristoylated and has not been detected in mature virions, supposedly owing to its small size By similarity. VP1-2A precursor is a component of immature procapsids and corresponds to an extended form of the structural protein VP1. The C-terminal domain of VP1-2A, protein 2A, acts as an assembly signal that allows multimerization of VP1-2A and formation of pentamers of VP1-VP2-VP3 trimers. It is proteolytically removed from the precursor by a host protease and does not seem to be found in mature particles By similarity. Protein 2B and 2BC precursor affect membrane integrity and cause an increase in membrane permeability By similarity. Protein 2C associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities By similarity. Protein 3A, via its hydrophobic domain, serves as membrane anchor to the 3AB and 3ABC precursors By similarity. The 3AB precursor interacts with the 3CD precursor and with RNA structures found at both the 5'- and 3'-termini of the viral genome. Since the 3AB precursor contains the hydrophobic domain 3A, it probably anchors the whole viral replicase complex to intracellular membranes on which viral RNA synthesis occurs By similarity. The 3ABC precursor is targeted to the mitochondrial membrane where protease 3C activity cleaves and inhibits the host antiviral protein MAVS, thereby disrupting activation of IRF3 through the IFIH1/MDA5 pathway. In vivo, the protease activity of 3ABC precursor is more efficient in cleaving the 2BC precursor than that of protein 3C. The 3ABC precursor may therefore play a role in the proteolytic processing of the polyprotein By similarity. Protein 3B is covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. It acts as a genome-linked replication primer By similarity. Protein 3C is a cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind co-operatively to the protease. Also cleaves host proteins such as PCBP2 By similarity. RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals By similarity.
Catalytic activity	Nucleoside triphosphate + RNA(n) = diphosphate + RNA(n+1). Selective cleavage of Gln-|-Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly. NTP + H2O = NDP + phosphate.
Subunit structure	3AB precursor is a homodimer. 3AB precursor interacts with 3CD precursor. Protein 3ABC interacts with human MAVS By similarity.
Subcellular location	Protein VP2: Virion By similarity. Host cytoplasm Potential. Protein VP3: Virion By similarity. Host cytoplasm Potential. Protein VP1: Virion By similarity. Host cytoplasm Potential. Protein VP1-2A: Virion By similarity. Host cytoplasm Potential. Protein 2B: Host cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side Potential. Note: Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum By similarity. Protein 2C: Host cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side Potential. Note: Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum. May associate with membranes through a N-terminal amphipathic helix By similarity. Protein 3ABC: Host cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side Potential. Host mitochondrion outer membrane; Peripheral membrane protein; Cytoplasmic side Potential. Note: Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum By similarity. Protein 3AB: Host cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side Potential. Note: Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum By similarity. Protein 3A: Host cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side Potential. Note: Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum By similarity. Protein 3B: Virion Potential. Picornain 3C: Host cytoplasm Potential. RNA-directed RNA polymerase 3D-POL: Host cytoplasmic vesicle membrane; Peripheral membrane protein; Cytoplasmic side Potential. Note: Interacts with membranes in a complex with viral protein 3AB. Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum By similarity.
Post-translational modification	Specific enzymatic cleavages by the viral protease in vivo yield a variety of precursors and mature proteins. Polyprotein processing intermediates are produced, such as P1-2A which is a functional precursor of the structural proteins, VP0 which is a VP4-VP2 precursor, VP1-2A precursor, 3ABC precursor which is a stable and catalytically active precursor of 3A, 3B and 3C proteins, 3AB and 3CD precursors. The assembly signal 2A is removed from VP1-2A by a host protease. During virion maturation, non-infectious particles are rendered infectious following cleavage of VP0. This maturation cleavage is followed by a conformational change of the particle By similarity. VPg is uridylylated by the polymerase and is covalently linked to the 5'-end of genomic RNA. This uridylylated form acts as a nucleotide-peptide primer for the polymerase By similarity.
Sequence similarities	Belongs to the picornaviridae polyprotein family. Contains 1 peptidase C3 domain. Contains 1 RdRp catalytic domain.
Caution	It is uncertain whether Met-1 or Met-3 is the initiator. Protein VP1 seems to have a heterogeneous C-terminus in cell culture. It may be reduced by a few amino acids compared to the sequence shown.

Ontologies

Keywords
Biological process	Host-virus interaction Interferon antiviral system evasion RNA replication
Cellular component	Capsid protein Cytoplasm Cytoplasmic vesicle Membrane Mitochondrion Mitochondrion outer membrane Virion
Domain	Coiled coil
Ligand	ATP-binding Nucleotide-binding RNA-binding
Molecular function	Helicase Hydrolase Nucleotidyltransferase Protease RNA-directed RNA polymerase Thiol protease Transferase
PTM	Covalent protein-RNA linkage Phosphoprotein
Gene Ontology (GO)
Biological process	RNA-protein covalent cross-linking Inferred from electronic annotation. Source: UniProtKB-KW evasion by virus of host immune response Inferred from electronic annotation. Source: UniProtKB-KW proteolysis Inferred from electronic annotation. Source: InterPro transcription, RNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW viral genome replication Inferred from electronic annotation. Source: InterPro
Cellular component	cytoplasmic vesicle Inferred from electronic annotation. Source: UniProtKB-KW host cell cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrial outer membrane Inferred from electronic annotation. Source: UniProtKB-KW viral capsid Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW RNA binding Inferred from electronic annotation. Source: UniProtKB-KW RNA-directed RNA polymerase activity Inferred from electronic annotation. Source: UniProtKB-KW cysteine-type endopeptidase activity Inferred from electronic annotation. Source: InterPro helicase activity Inferred from electronic annotation. Source: UniProtKB-KW structural molecule activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 2052	2052	Genome polyprotein		PRO_0000311062
	Chain	1 – 245	245	Protein VP0 Potential		PRO_0000311063
	Chain	1 – 23	23	Protein VP4 Potential		PRO_5000145525
	Chain	24 – 245	222	Protein VP2 Potential		PRO_5000145526
	Chain	246 – 491	246	Protein VP3 Potential		PRO_5000145527
	Chain	492 – 830	339	Protein VP1-2A Potential		PRO_0000311064
	Chain	492 – 763	272	Protein VP1 Potential		PRO_5000145528
	Chain	764 – 830	67	Protein 2A Potential		PRO_5000145529
	Chain	831 – 1258	428	Protein 2BC Potential		PRO_0000311065
	Chain	831 – 1081	251	Protein 2B Potential		PRO_5000145530
	Chain	1082 – 1258	177	Protein 2C Potential		PRO_5000145531
	Chain	1259 – 2052	794	Protein 3ABCD Potential		PRO_0000311066
	Chain	1259 – 1572	314	Protein 3ABC Potential		PRO_0000311067
	Chain	1259 – 1353	95	Protein 3AB Potential		PRO_0000311068
	Chain	1259 – 1330	72	Protein 3A Potential		PRO_5000145521
	Chain	1331 – 1353	23	Protein 3B Potential		PRO_5000145522
	Chain	1354 – 2052	699	Protein 3CD Potential		PRO_0000311069
	Chain	1354 – 1572	219	Picornain 3C Potential		PRO_5000145523
	Chain	1573 – 2052	480	RNA-directed RNA polymerase 3D-POL Potential		PRO_5000145524
Regions
	Topological domain	1 – 1301	1301	Cytoplasmic Potential
	Topological domain	1302 – 1316	15	In membrane Potential
	Topological domain	1317 – 2052	736	Cytoplasmic Potential
	Domain	1354 – 1550	197	Peptidase C3
	Domain	1810 – 1931	122	RdRp catalytic
	Coiled coil	1121 – 1146	26	Potential
Sites
	Active site	1397	1	For picornain 3C activity By similarity
	Active site	1437	1	For picornain 3C activity By similarity
	Active site	1525	1	For picornain 3C activity By similarity
	Site	23 – 24	2	Cleavage Potential
	Site	245 – 246	2	Cleavage; by picornain 3C Potential
	Site	491 – 492	2	Cleavage; by picornain 3C Potential
	Site	763 – 764	2	Cleavage; by host Potential
	Site	763	1	Important for VP1 folding and capsid assembly By similarity
	Site	830 – 831	2	Cleavage; by picornain 3C By similarity
	Site	1081 – 1082	2	Cleavage; by picornain 3C Potential
	Site	1258 – 1259	2	Cleavage; by picornain 3C Potential
	Site	1330 – 1331	2	Cleavage; by picornain 3C Potential
	Site	1353 – 1354	2	Cleavage; by picornain 3C Potential
	Site	1572 – 1573	2	Cleavage; by picornain 3C By similarity
Amino acid modifications
	Modified residue	1333	1	O-(5'-phospho-RNA)-tyrosine By similarity
Experimental info
	Non-adjacent residues	1161 – 1162	2

Sequences

	Sequence		Length	Mass (Da)
	Q05794-1 [UniParc]. Last modified November 13, 2007. Version 2. Checksum: 971E03905B81110A	FASTA	2,052	231,976
	10 20 30 40 50 60 MNMSKQGIFQ TVGSGLDHIL SLADIEEEQM IQSVDRTAVT GASYFTSVDQ SSVHTAEVGS 70 80 90 100 110 120 HQIEPLKTSV DKPGSKKTQG EKFFLIHSAD WLTTHALFHE VAKLDVVKLL YNEQFAVQGL 130 140 150 160 170 180 LRYHTYARFG IEIQVQINPT PFQQGGLICA MVPGDQSYGS IASLTVYPHG LLNCNINNVV 190 200 210 220 230 240 RIKVPFIYTR GAYHFKDPQY PVWELTIRVW SELNIGTGTS AYTSLNVLAR FTDLELHGLT 250 260 270 280 290 300 PLSTQMMRNE FRVSTTENVV NLSNYEDARA KMSFALDQED WKSDPSQGGG IKITHFTTWT 310 320 330 340 350 360 SIPTLAAQFP FNASDSVGQQ IKVIPVDPYF FQMTNTNPDQ KCITALASIC QMFCFWRGDL 370 380 390 400 410 420 VFDFQVFPTK YHSGRLLFCF VPGNELIDVT GITLKQATTA PCAVMDITGV QSTLRFRVPW 430 440 450 460 470 480 ISDTPYRVNR YTKSAHQKGE YTAIGKLIVY CYNRLTSPSN VASHVRVNVY LSAINLECFA 490 500 510 520 530 540 PLYHAMDVTT QVGDDSGGFS TTVSTEQNVP DPQVGIKGKA NRGKMDVSGV QAPVGAITTI 550 560 570 580 590 600 EDPVLAKKVP ETFPELKPGE SRHTSDHMSI YKFMGRSHFL CTFTFNSNNK EYTFPITLSS 610 620 630 640 650 660 TSNPPHGLPS TLRWFFNLFQ LYRGPLDLTI IITGATDVDG MAWFTPVGLA VDTPWVEKKS 670 680 690 700 710 720 ALSIDYKTAL GAVRFNTRRT GNIQIRLPWY SYLYAVSGAL DGLGDKTDST FGLVSIQIAN 730 740 750 760 770 780 YNHSDEYLSF SCYLSVTEQS EFYFPRAPLN SNAMLSTESM MSRIAAGDLE SSVDDPRSEE 790 800 810 820 830 840 DRRFESHIEC RKPYKELRLE VGKQRLKYAQ EELSNEVLPP PRKMKGLFSQ AKISLFYTEE 850 860 870 880 890 900 HEIMKFSWRG VTADTRALRR FGFSLAAGRS VWTLEMDAGV LTGRLIRLND EKWTEMKDDK 910 920 930 940 950 960 IVSLIEKFTS NKYWSKVNFP HGMLDLEEIA ANSKDFPNMS ETDLCFLLHW LNPKKINLAD 970 980 990 1000 1010 1020 RMLGLSGVQE IKEQGVGLIA ECRTFLDSIA GTLKSMIFGF HHSVTVEIIN IVLCFIKSGI 1030 1040 1050 1060 1070 1080 LLYVIQQLNQ DEHSHIIGLL RVMNYADIGC SVISCGKVFS KMLETVFNWQ MDSRMMELRT 1090 1100 1110 1120 1130 1140 QSFSNWLRDI CSGITIFKSF KDAIYWLCTK LKDFYEVNYG KKKDVLNILK DNQQKIEKAI 1150 1160 1170 1180 1190 1200 EEADNFCILQ IQDVEKFDQY QTSNWSNPSP KTVYVKEAID RRLHFKVEVK PASFFKNPHN 1210 1220 1230 1240 1250 1260 DMLNVNLAKT NDAIKDMSCV DLIMDGHNIS LMDLLSSLVM TVEIRKQNMS EFMELWSQGI 1270 1280 1290 1300 1310 1320 SDDDSAVAEF FQSFPSGEPS NSKLSSFFQS VTNHKWVAVG AAVGILGLLV GGWFVYKHFS 1330 1340 1350 1360 1370 1380 RKEEEPIPAE GVYHGVTKPK QVIKLDADPV ESQSTLEIAG LVRKNLVQFG VGEKNGCVRW 1390 1400 1410 1420 1430 1440 VMNALGVKDD WLLVPSHAYK FEKDYEMMEF YFNRGGTYYS ISAGNVVIQS LDVGFQDVVL 1450 1460 1470 1480 1490 1500 MKVPTIPKFR DITQHFIKKG DVPRALNRLA TLVTTVNGTP MLISEGPLKM EEKATYVHKK 1510 1520 1530 1540 1550 1560 NDGTTVDLTV DQAWRGKGEG LPGMCGGALV SSNQSIQNAI LGIHVAGGNS ILVAKLITQE 1570 1580 1590 1600 1610 1620 MFQNIDKKIE SQRIMKVEFT QCSMNVVSKT LFRKSPIHHH IDKTMINFPA AMPFSKAEID 1630 1640 1650 1660 1670 1680 PMAMMLSKYS LPIVEEPEDY KEASVFYQNK IVGKTQLVDD FLDLDMAITG APGIDAINMD 1690 1700 1710 1720 1730 1740 SSPGFPYVQE KLTKRDLIWL DENGLLLGVH PRLAQRILFN TVMMENCSDL DVVFTTCPKD 1750 1760 1770 1780 1790 1800 ELRPLEKVLE SKTRAIDACP LDYTILCRMY WGPAISYFHL NPGFHTGVAI GIDPDRQWDE 1810 1820 1830 1840 1850 1860 LFKTMIRFGD VGLDLDFSAF DASLSPFMIR EAGRIMSELS GTPSHFGTAL INTIIYSKHL 1870 1880 1890 1900 1910 1920 LYNCCYHVCG SMPSGSPCTA LLNSIINNIN LYYVFSKIFG KSPVFFCQAL RILCYGDDVL 1930 1940 1950 1960 1970 1980 IVFSRDVQID NLDLIGQKIV DEFKKLGMTA TSADKNVPQL KPVSELTFLK RSFNLVEDRI 1990 2000 2010 2020 2030 2040 RPAISEKTIW SLIAWQRSNA EFEQNLENAQ WFAFMHGYEF YQKFYYFVQS CLEKEMIEYR 2050 LKSYDWWRMR FY

References

[1]	"Cloning and expression of hepatitis A virus genome in E. coli cells." Sverdlov S.D., Tsarev S.A., Markova S.V., Vasilenko S.K., Chizhikov V.E., Petrov N.A., Kusov Y.Y., Nastashenko T.A., Balayan M.S. Mol. Genet. Microbiol. Virol. 6:129-133(1987) Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA].
[2]	"Sequence of 3372 RNA nucleotide links in the hepatitis A virus coding for capsid VP4-VP1 and nonstructural proteins." Ovchinnikov Y.A., Sverdlov E.D., Tsarev S.A., Arsenian S.G., Rokhlina T.O. Dokl. Akad. Nauk SSSR 285:1014-1018(1985) [PubMed: 3000718] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1-906.
[3]	"Genetic relatedness of hepatitis A virus strains recovered from different geographical regions." Robertson B.H., Jansen R.W., Khanna B., Totsuka A., Nainan O.V., Siegl G., Widell A., Margolis H.S., Isomura S., Ito K., Ishizu T., Moritsugu Y., Lemon S.M. J. Gen. Virol. 73:1365-1377(1992) [PubMed: 1318940] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 758-813.

Cross-references

Sequence databases
EMBLGenBankDDBJ	X15463 Genomic RNA. Translation: CAA33491.1. X15464 Genomic RNA. Translation: CAA33492.1. L07669 Genomic RNA. No translation available.
3D structure databases
HSSP	HSSP built from PDB template 1QA7 based on UniProtKB P26582.
ModBase	Search...
Family and domain databases
InterPro	IPR004004. Helicase/Pol/Pept_Calicivir. IPR000199. Pept_C3_picorn. IPR001676. Picornavirus_capsid. IPR001205. RNA_pol_P3D. IPR007094. RNA_pol_PSvir. [Graphical view]
Pfam	PF00548. Peptidase_C3. 1 hit. PF00680. RdRP_1. 1 hit. PF00073. Rhv. 2 hits. [Graphical view]
PRINTS	PR00918. CALICVIRUSNS.
PROSITE	PS50507. RDRP_SSRNA_POS. 1 hit. [Graphical view]
ProtoNet	Search...

Entry information

Entry name

POLG_HAVHA

Accession

Primary (citable) accession number: Q05794
Secondary accession number(s): Q67800 , Q67801, Q67802, Q67803, Q67804, Q67805, Q67806, Q67807

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 13, 2007
Last sequence update:	November 13, 2007
Last modified:	June 16, 2009
This is version 42 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

Virus (Virus annotation project)