ID   POLN_HEVME              Reviewed;        1691 AA.
AC   Q03495;
DT   01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1993, sequence version 1.
DT   03-AUG-2022, entry version 108.
DE   RecName: Full=Non-structural polyprotein pORF1;
DE   Includes:
DE     RecName: Full=Methyltransferase;
DE              EC=2.1.1.-;
DE              EC=2.7.7.-;
DE   Includes:
DE     RecName: Full=Putative papain-like cysteine protease;
DE              Short=PLP;
DE              EC=3.4.22.-;
DE   Includes:
DE     RecName: Full=NTPase/helicase;
DE              EC=3.6.4.-;
DE   Includes:
DE     RecName: Full=RNA-directed RNA polymerase;
DE              Short=RdRp;
DE              EC=2.7.7.48;
GN   ORFNames=ORF1;
OS   Hepatitis E virus genotype 2 (isolate Human/Mexico) (HEV-2).
OC   Viruses; Riboviria; Orthornavirae; Kitrinoviricota; Alsuviricetes;
OC   Hepelivirales; Hepeviridae; Orthohepevirus; Hepatitis E virus.
OX   NCBI_TaxID=31768;
OH   NCBI_TaxID=69079; Bandicota bengalensis (lesser bandicoot rat).
OH   NCBI_TaxID=9481; Callithrix.
OH   NCBI_TaxID=9536; Cercopithecus hamlyni (Owl-faced monkey) (Hamlyn's monkey).
OH   NCBI_TaxID=9534; Chlorocebus aethiops (Green monkey) (Cercopithecus aethiops).
OH   NCBI_TaxID=9031; Gallus gallus (Chicken).
OH   NCBI_TaxID=9606; Homo sapiens (Human).
OH   NCBI_TaxID=9539; Macaca (macaques).
OH   NCBI_TaxID=10090; Mus musculus (Mouse).
OH   NCBI_TaxID=9598; Pan troglodytes (Chimpanzee).
OH   NCBI_TaxID=9520; Saimiri (squirrel monkeys).
OH   NCBI_TaxID=9823; Sus scrofa (Pig).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=1448913; DOI=10.1016/0042-6822(92)90230-m;
RA   Huang C.C., Nguyen D., Fernandez J., Yun K.Y., Fry K.E., Bradley D.W.,
RA   Tam A.W., Reyes G.R.;
RT   "Molecular cloning and sequencing of the Mexico isolate of hepatitis E
RT   virus (HEV).";
RL   Virology 191:550-558(1992).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 965-1691.
RX   PubMed=1589964; DOI=10.1007/bf01703066;
RA   Fry K.E., Tam A.W., Smith M.M., Kim J.P., Luk K.-C., Young L.M., Piatak M.,
RA   Feldman R.A., Yun K.Y., Purdy M.A., McCaustland K.A., Bradley D.W.,
RA   Reyes G.R.;
RT   "Hepatitis E virus (HEV): strain variation in the nonstructural gene region
RT   encoding consensus motifs for an RNA-dependent RNA polymerase and an
RT   ATP/GTP binding site.";
RL   Virus Genes 6:173-185(1992).
CC   -!- FUNCTION: Methyltransferase: Displays a capping enzyme activity. This
CC       function is necessary since all viral RNAs are synthesized in the
CC       cytoplasm, and host capping enzymes are restricted to the nucleus. The
CC       enzymatic reaction involves a covalent link between 7-methyl-GMP and
CC       the methyltransferase, whereas eukaryotic capping enzymes form a
CC       covalent complex only with GMP. Methyltransferase catalyzes transfer of
CC       a methyl group from S-adenosylmethionine to GTP and GDP to yield
CC       m(7)GTP or m(7)GDP. This enzyme also displays guanylyltransferase
CC       activity to form a covalent complex, methyltransferase-m(7)GMP, from
CC       which 7-methyl-GMP is transferred to the mRNA to create the cap
CC       structure. {ECO:0000250|UniProtKB:Q81862}.
CC   -!- FUNCTION: Papain-like cysteine protease: May participate in the
CC       processing of polyprotein pORF1 together with cellular proteases and
CC       the cleavage of capsid protein ORF2. {ECO:0000250|UniProtKB:Q81862}.
CC   -!- FUNCTION: NTPase/helicase: Multi-functional protein that exhibits
CC       NTPase and RNA unwinding activities. Hydrolyzes all NTPs efficiently
CC       and unwinds RNA duplexes containing 5' overhangs. Possesses a sequence
CC       independent RNA-5'-triphosphatase (RTPase) activity suggestive of its
CC       role in forming viral cap structure (By similarity). Participates also
CC       in viral genome replication, RNA translocation and genome
CC       packaging/unpackaging (By similarity). {ECO:0000250|UniProtKB:P29324,
CC       ECO:0000250|UniProtKB:Q81862}.
CC   -!- FUNCTION: RNA-directed RNA polymerase: Plays an essential role in the
CC       virus replication. Binds to the 3'-end of the genomic RNA to initiate
CC       viral replication. {ECO:0000250|UniProtKB:Q81862}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC         RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-
CC         COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395;
CC         EC=2.7.7.48; Evidence={ECO:0000250|UniProtKB:Q81862};
CC   -!- SUBCELLULAR LOCATION: Host cytoplasm {ECO:0000250|UniProtKB:Q81862}.
CC   -!- PTM: It is not yet clear whether the ORF1-encoded polyprotein contains
CC       multiple biochemical activities, or undergoes cis or trans- processing
CC       to release biochemically distinct peptides. No processing has been
CC       observed in mammalian expression systems. However, the baculovirus
CC       expressed polyprotein is processed into smaller protein, probably by a
CC       cysteine protease.
CC   -!- SIMILARITY: Belongs to the hepevirus non-structural polyprotein family.
CC       {ECO:0000305}.
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DR   EMBL; M74506; AAA45730.1; -; Genomic_RNA.
DR   PIR; A44212; A44212.
DR   SMR; Q03495; -.
DR   PRIDE; Q03495; -.
DR   Proteomes; UP000007245; Genome.
DR   GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0008234; F:cysteine-type peptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0004386; F:helicase activity; IEA:UniProtKB-KW.
DR   GO; GO:0008174; F:mRNA methyltransferase activity; IEA:InterPro.
DR   GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR   GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IEA:UniProtKB-KW.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   GO; GO:0006396; P:RNA processing; IEA:InterPro.
DR   GO; GO:0006351; P:transcription, DNA-templated; IEA:InterPro.
DR   GO; GO:0019082; P:viral protein processing; IEA:InterPro.
DR   GO; GO:0039694; P:viral RNA genome replication; IEA:InterPro.
DR   CDD; cd21557; Macro_X_Nsp3-like; 1.
DR   Gene3D; 3.40.220.10; -; 1.
DR   Gene3D; 3.40.50.300; -; 2.
DR   InterPro; IPR027351; (+)RNA_virus_helicase_core_dom.
DR   InterPro; IPR002588; Alphavirus-like_MT_dom.
DR   InterPro; IPR043502; DNA/RNA_pol_sf.
DR   InterPro; IPR008748; Hepatitis-E_Cys-pept.
DR   InterPro; IPR022202; Hepatitis-E_hinge.
DR   InterPro; IPR002589; Macro_dom.
DR   InterPro; IPR043472; Macro_dom-like.
DR   InterPro; IPR044371; Macro_X_NSP3-like.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR007094; RNA-dir_pol_PSvirus.
DR   InterPro; IPR001788; Tymovirus_RNA-dep_RNA_pol.
DR   Pfam; PF12526; DUF3729; 1.
DR   Pfam; PF05417; Peptidase_C41; 1.
DR   Pfam; PF00978; RdRP_2; 1.
DR   Pfam; PF01443; Viral_helicase1; 1.
DR   Pfam; PF01660; Vmethyltransf; 1.
DR   SMART; SM00506; A1pp; 1.
DR   SUPFAM; SSF52540; SSF52540; 1.
DR   SUPFAM; SSF52949; SSF52949; 1.
DR   SUPFAM; SSF56672; SSF56672; 1.
DR   PROSITE; PS51743; ALPHAVIRUS_MT; 1.
DR   PROSITE; PS51154; MACRO; 1.
DR   PROSITE; PS51657; PSRV_HELICASE; 1.
DR   PROSITE; PS50507; RDRP_SSRNA_POS; 1.
PE   3: Inferred from homology;
KW   ATP-binding; Helicase; Host cytoplasm; Hydrolase; Methyltransferase;
KW   Nucleotide-binding; Nucleotidyltransferase; Protease; RNA-binding;
KW   RNA-directed RNA polymerase; Thiol protease; Transferase;
KW   Viral RNA replication.
FT   CHAIN           1..1691
FT                   /note="Non-structural polyprotein pORF1"
FT                   /id="PRO_0000100133"
FT   DOMAIN          56..240
FT                   /note="Alphavirus-like MT"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01079"
FT   DOMAIN          773..919
FT                   /note="Macro"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00490"
FT   DOMAIN          932..1080
FT                   /note="(+)RNA virus helicase ATP-binding"
FT   DOMAIN          1081..1214
FT                   /note="(+)RNA virus helicase C-terminal"
FT   DOMAIN          1452..1563
FT                   /note="RdRp catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT   REGION          60..240
FT                   /note="Methyltransferase"
FT                   /evidence="ECO:0000250"
FT   REGION          239..439
FT                   /note="Y-domain"
FT                   /evidence="ECO:0000250"
FT   REGION          440..610
FT                   /note="Putative papain-like cysteine protease"
FT                   /evidence="ECO:0000250"
FT   REGION          710..776
FT                   /note="Hinge"
FT                   /evidence="ECO:0000250"
FT   REGION          722..778
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          783..940
FT                   /note="X-domain"
FT                   /evidence="ECO:0000250"
FT   REGION          958..1202
FT                   /note="NTPase/helicase"
FT                   /evidence="ECO:0000250"
FT   REGION          1205..1691
FT                   /note="RNA-directed RNA polymerase"
FT                   /evidence="ECO:0000250"
FT   BINDING         973..980
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   1691 AA;  185225 MW;  DB3F0B2C913F871B CRC64;
     MEAHQFIKAP GITTAIEQAA LAAANSALAN AVVVRPFLSH QQVEILINLM QPRQLVFRPE
     VFWNHPIQRV IHNELEQYCR ARSGRCLEIG AHPRSINDNP NVLHRCFLHP VGRDVQRWYT
     APTRGPAANC RRSALRGLPP ADRTYCFDGF AGCRFAAETG VALYSLHDLQ PADVAEAMAR
     HGMTRLYAAF HLPPEVLLPP GTYRTSSYLL IHDGKRAVVT YEGDTSAGYN HDVATLRTWI
     RTTKVVGEHP LVIERVRGIG CHFVLLITAA PEPSPMPYVP YPRSTEVYVR SIFGPGGSPS
     LFPTACAVKS TFHAVPTHIW DRLMLFGATL DDQAFCCSRL MTYLRGISYK VTVGALVANE
     GWNATEDALT AVITAAYLTI CHQRYLRTQA ISKGMRRLEL EHAQKFISRL YSWLFEKSGR
     DYIPGRQLQF YAQCRRWLSA GFHLDPRTLV FDESVPCSCR TTIRRIAGKF CCFMKWLGQE
     CSCFLQPAEG LAGDQGHDNE AYEGSDVDTA EPATLDITGS YIVDGRSLQT VYQALDLPAD
     LVARAARLSA TVTVTETSGR LDCQTMIGNK TFLTTFVDGA RLEVNGPEQL NLSFDSQQCS
     MAAGPFCLTY AAVDGGLEVH FSTAGLESRV VFPPGNAPTA PPSEVTAFCS ALYRHNRQSQ
     RQSVIGSLWL HPEGLLGLFP PFSPGHEWRS ANPFCGESTL YTRTWSTITD TPLTVGLISG
     HLDAAPHSGG PPATATGPAV GSSDSPDPDP LPDVTDGSRP SGARPAGPNP NGVPQRRLLH
     TYPDGAKIYV GSIFESECTW LVNASNAGHR PGGGLCHAFF QRYPDSFDAT KFVMRDGLAA
     YTLTPRPIIH AVAPDYRLEH NPKRLEAAYR ETCARRGTAA YPLLGAGIYQ VPVSLSFDAW
     ERNHRPFDEL YLTELAARWF ESNRPGQPTL NITEDTARAA NLALELDSGS EVGRACAGCK
     VEPGVVRYQF TAGVPGSGKS KSVQQADVDV VVVPTRELRN AWRRRGFAAF TPHTAARVTS
     GRRVVIDEAP SLPPHLLLLH MQRAASVHLL GDPNQIPAID FEHTGLIPAI RPELVPTSWW
     HVTHRCPADV CELVRGAYPK IQTTSKVLRS LFWGEPAVGQ KLVFTQAAKA AHPGSITVHE
     AQGATFTTTT IIATADARGL IQSSRAHAIV ALTRHTEKCV ILDSPGLLRE VGISDAIVNN
     FFLSGGEVGH QRPSVIPRGN PDRNVDVLAA FPPSCQISAF HQLAEELGHR PAPVAAVLPP
     CPELEQGLLY LPQELASCDS VVTFELTDIV HCRMAAPSQR KAVLSTLVGR YGRRTRLYDA
     GHTDVRASLA RFIPTLGRVT ATTCELFELV EAMVEKGQDG SAVLELDLCS RDVSRITFFQ
     KDCNKFTTGE TIAHGKVGQG IFRWSKTFCA LFGPWFRAIE KAILSLLPQA VFYGDAYDDS
     VFSAAVAGAS HAMVFENDFS EFDSTQNNFS LGLECAIMEE CGMPQWLVRL YHAVRSAWIL
     QAPKESLRGF WKKHSGEPGS LLWNTVWNMA IIAHCYEFRD LQVAAFKGDD SVVLCSEYRQ
     SPGAGSLIAG CGLKLKADFR PIGLYAGVVV APGLGALPDV VRFAGRLSEK NWGPDPERAE
     QLRLAVQDFL RRLTNVAQIC VEVVSRVYGV SPGLVHNLIG MLQTIGDGKA HFTESVKPIL
     DLTHSIMHRS E