ID   L_RVFVZ                 Reviewed;        2149 AA.
AC   P27316;
DT   01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT   01-AUG-1992, sequence version 1.
DT   24-JAN-2024, entry version 85.
DE   RecName: Full=RNA-directed RNA polymerase L;
DE            Short=Protein L;
DE            EC=2.7.7.48 {ECO:0000269|PubMed:34787453};
DE   AltName: Full=Large structural protein;
DE   AltName: Full=Replicase;
DE   AltName: Full=Transcriptase;
DE   Includes:
DE     RecName: Full=cap-snatching endonuclease;
DE              EC=3.1.-.- {ECO:0000250|UniProtKB:I0DF35};
GN   Name=L;
OS   Rift valley fever virus (strain ZH-548 M12) (RVFV).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC   Ellioviricetes; Bunyavirales; Phenuiviridae; Phlebovirus;
OC   Phlebovirus riftense.
OX   NCBI_TaxID=11589;
OH   NCBI_TaxID=7158; Aedes.
OH   NCBI_TaxID=9913; Bos taurus (Bovine).
OH   NCBI_TaxID=297284; Bos taurus x Bison bison (beefalo).
OH   NCBI_TaxID=9837; Camelus bactrianus (Bactrian camel).
OH   NCBI_TaxID=9925; Capra hircus (Goat).
OH   NCBI_TaxID=9606; Homo sapiens (Human).
OH   NCBI_TaxID=9940; Ovis aries (Sheep).
OH   NCBI_TaxID=29031; Phlebotomus papatasi (Sandfly).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=1923828; DOI=10.1093/nar/19.19.5433;
RA   Mueller R., Argentini C., Bouloy M., Prehaud C., Bishop D.H.L.;
RT   "Completion of the genome sequence of Rift Valley fever phlebovirus
RT   indicates that the L RNA is negative sense and codes for a putative
RT   transcriptase-replicase.";
RL   Nucleic Acids Res. 19:5433-5433(1991).
RN   [2]
RP   SUBUNIT.
RC   STRAIN=MP12;
RX   PubMed=19812169; DOI=10.1128/jvi.01310-09;
RA   Zamoto-Niikura A., Terasaki K., Ikegami T., Peters C.J., Makino S.;
RT   "Rift valley fever virus L protein forms a biologically active oligomer.";
RL   J. Virol. 83:12779-12789(2009).
RN   [3]
RP   INTERACTION WITH GLYCOPROTEIN N.
RX   PubMed=21445316; DOI=10.1371/journal.pone.0018070;
RA   Piper M.E., Sorenson D.R., Gerrard S.R.;
RT   "Efficient cellular release of Rift Valley fever virus requires genomic
RT   RNA.";
RL   PLoS ONE 6:E18070-E18070(2011).
RN   [4]
RP   FUNCTION.
RX   PubMed=23824541; DOI=10.1101/gad.215384.113;
RA   Hopkins K.C., McLane L.M., Maqbool T., Panda D., Gordesky-Gold B.,
RA   Cherry S.;
RT   "A genome-wide RNAi screen reveals that mRNA decapping restricts bunyaviral
RT   replication by limiting the pools of Dcp2-accessible targets for cap-
RT   snatching.";
RL   Genes Dev. 27:1511-1525(2013).
RN   [5]
RP   FUNCTION, AND MUTAGENESIS OF ASP-111.
RX   PubMed=23698297; DOI=10.1128/jvi.00371-13;
RA   Klemm C., Reguera J., Cusack S., Zielecki F., Kochs G., Weber F.;
RT   "Systems to establish bunyavirus genome replication in the absence of
RT   transcription.";
RL   J. Virol. 87:8205-8212(2013).
RN   [6]
RP   REVIEW.
RX   PubMed=28418734; DOI=10.1080/1040841x.2017.1307805;
RA   Amroun A., Priet S., de Lamballerie X., Querat G.;
RT   "Bunyaviridae RdRps: structure, motifs, and RNA synthesis machinery.";
RL   Crit. Rev. Microbiol. 43:753-778(2017).
RN   [7]
RP   REVIEW.
RX   PubMed=31948728; DOI=10.1016/j.tim.2019.12.006;
RA   Olschewski S., Cusack S., Rosenthal M.;
RT   "The Cap-Snatching Mechanism of Bunyaviruses.";
RL   Trends Microbiol. 28:293-303(2020).
RN   [8]
RP   INTERACTION WITH NUCLEOPROTEIN N.
RX   PubMed=33952635; DOI=10.1128/jvi.00429-21;
RA   Tercero B., Narayanan K., Terasaki K., Makino S.;
RT   "Characterization of the Molecular Interactions That Govern the Packaging
RT   of Viral RNA Segments into Rift Valley Fever Phlebovirus Particles.";
RL   J. Virol. 95:e0042921-e0042921(2021).
RN   [9]
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) OF 216-, COFACTOR,
RP   CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-111.
RX   PubMed=34787453; DOI=10.1128/jvi.01713-21;
RA   Wang X., Hu C., Ye W., Wang J., Dong X., Xu J., Li X., Zhang M., Lu H.,
RA   Zhang F., Wu W., Dai S., Wang H.W., Chen Z.;
RT   "Structure of Rift Valley Fever Virus RNA-Dependent RNA Polymerase.";
RL   J. Virol. 96:e0171321-e0171321(2022).
CC   -!- FUNCTION: RNA-dependent RNA polymerase, which is responsible for the
CC       replication and transcription of the viral RNA genome using antigenomic
CC       RNA as an intermediate (PubMed:23698297). During transcription,
CC       synthesizes subgenomic RNAs and assures their capping by a cap-
CC       snatching mechanism, which involves the endonuclease activity cleaving
CC       the host capped pre-mRNAs (PubMed:23824541). These short capped RNAs
CC       are then used as primers for viral transcription. The 3'-end of
CC       subgenomic mRNAs molecules are not polyadenylated. During replication,
CC       the polymerase binds the 5' and 3' vRNA extremities at distinct sites
CC       (By similarity). In turn, significant conformational changes occur in
CC       the polymerase and in vRNA to initiate active RNA synthesis (By
CC       similarity). As a consequence of the use of the same enzyme for both
CC       transcription and replication, these mechanisms need to be well
CC       coordinated (By similarity). {ECO:0000250|UniProtKB:A5HC98,
CC       ECO:0000250|UniProtKB:I0DF35, ECO:0000269|PubMed:23698297,
CC       ECO:0000269|PubMed:23824541}.
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:0000255|PROSITE-ProRule:PRU00539,
CC         ECO:0000269|PubMed:34787453};
CC   -!- COFACTOR:
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000269|PubMed:34787453};
CC       Note=For endonuclease activity. Binds 2 Mn(2+) ions in the active site
CC       (PubMed:34787453). The divalent metal ions are crucial for catalytic
CC       activity (PubMed:31948728). {ECO:0000269|PubMed:31948728,
CC       ECO:0000269|PubMed:34787453};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:34787453};
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000269|PubMed:34787453};
CC       Note=For polymerase activity. Initiation activity is stronger in the
CC       presence of Mn(2+) than in the presence of Mg(2+).
CC       {ECO:0000269|PubMed:34787453};
CC   -!- SUBUNIT: Homomultimer (PubMed:19812169). Interacts with glycoprotein N;
CC       this interaction allows efficient polymerase packaging into virus
CC       particles (PubMed:21445316). Interacts with nucleoprotein N
CC       (PubMed:33952635). {ECO:0000269|PubMed:19812169,
CC       ECO:0000269|PubMed:21445316, ECO:0000269|PubMed:33952635}.
CC   -!- SUBCELLULAR LOCATION: Host Golgi apparatus
CC       {ECO:0000250|UniProtKB:I0DF35}. Host endoplasmic reticulum
CC       {ECO:0000250|UniProtKB:I0DF35}. Host endoplasmic reticulum-Golgi
CC       intermediate compartment {ECO:0000250|UniProtKB:I0DF35}. Virion
CC       {ECO:0000250|UniProtKB:P20470}.
CC   -!- DOMAIN: The N-terminus contains the endonuclease activity (endoN) (By
CC       similarity). The central region contains the RdRp activity (By
CC       similarity). The C-terminus contains the cap-binding region (By
CC       similarity). {ECO:0000250|UniProtKB:A2SZS3,
CC       ECO:0000250|UniProtKB:A5HC98, ECO:0000250|UniProtKB:I0DF35}.
CC   -!- MISCELLANEOUS: Classified as His(+) endonuclease since it has a
CC       histidine upstream of the active site that coordinates the first
CC       cation. {ECO:0000303|PubMed:31948728}.
CC   -!- SIMILARITY: Belongs to the Bunyavirales RNA polymerase family.
CC       {ECO:0000305}.
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DR   EMBL; X56464; CAA39836.1; -; Genomic_RNA.
DR   PIR; S18676; S18676.
DR   PDB; 7EEI; X-ray; 3.60 A; A=216-1990.
DR   PDBsum; 7EEI; -.
DR   EMDB; EMD-31077; -.
DR   SMR; P27316; -.
DR   Proteomes; UP000002477; Genome.
DR   GO; GO:0044165; C:host cell endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR   GO; GO:0044172; C:host cell endoplasmic reticulum-Golgi intermediate compartment; IEA:UniProtKB-SubCell.
DR   GO; GO:0044177; C:host cell Golgi apparatus; IEA:UniProtKB-SubCell.
DR   GO; GO:0044423; C:virion component; IEA:UniProtKB-KW.
DR   GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0001882; F:nucleoside binding; IEA:InterPro.
DR   GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR   GO; GO:0003968; F:RNA-dependent RNA polymerase activity; IEA:UniProtKB-KW.
DR   GO; GO:0006351; P:DNA-templated transcription; IEA:InterPro.
DR   GO; GO:0039689; P:negative stranded viral RNA replication; ISS:UniProtKB.
DR   GO; GO:0039696; P:RNA-templated viral transcription; ISS:UniProtKB.
DR   InterPro; IPR022531; L_PA-C-like.
DR   InterPro; IPR029124; L_protein_N.
DR   InterPro; IPR007099; RNA-dir_pol_NSvirus.
DR   InterPro; IPR014385; RNA-dir_pol_phlebovirus.
DR   InterPro; IPR007322; RNA_pol_bunyavir.
DR   Pfam; PF04196; Bunya_RdRp; 1.
DR   Pfam; PF12603; L_PA-C-like; 1.
DR   Pfam; PF15518; L_protein_N; 1.
DR   PIRSF; PIRSF000826; L_PhleboV; 1.
DR   PROSITE; PS50525; RDRP_SSRNA_NEG_SEG; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Host endoplasmic reticulum; Host Golgi apparatus; Hydrolase;
KW   Magnesium; Manganese; Metal-binding; Nucleotide-binding;
KW   Nucleotidyltransferase; Reference proteome; RNA-directed RNA polymerase;
KW   Transferase; Viral RNA replication; Virion.
FT   CHAIN           1..2149
FT                   /note="RNA-directed RNA polymerase L"
FT                   /id="PRO_0000222023"
FT   DOMAIN          975..1166
FT                   /note="RdRp catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT   REGION          18..216
FT                   /note="Endonuclease"
FT                   /evidence="ECO:0000250|UniProtKB:A5HC98"
FT   REGION          1706..1822
FT                   /note="Cap-binding"
FT                   /evidence="ECO:0000250|UniProtKB:A5HC98"
FT   ACT_SITE        143
FT                   /note="For endonuclease activity"
FT                   /evidence="ECO:0000250|UniProtKB:I0DF35"
FT   BINDING         79
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:A5HC98"
FT   BINDING         111
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000305|PubMed:23698297"
FT   BINDING         111
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000305|PubMed:23698297"
FT   BINDING         125
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250|UniProtKB:A5HC98"
FT   BINDING         1134
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_note="catalytic; for RdRp activity"
FT                   /evidence="ECO:0000250|UniProtKB:I0DF35"
FT   MUTAGEN         111
FT                   /note="D->A: Loss of transcriptional activity but fully
FT                   active in replication."
FT                   /evidence="ECO:0000269|PubMed:23698297"
FT   MUTAGEN         111
FT                   /note="D->A: RNA synthesis products are still produced."
FT                   /evidence="ECO:0000269|PubMed:34787453"
SQ   SEQUENCE   2149 AA;  243591 MW;  8D5739C6079A88D7 CRC64;
     MDSILSKQLV DKTGFVRVPI KHFDCTMLTL ALPTFDVSKM VDRITIDFNL DDIQGASEIG
     STLLPSMSID VEDMANFVHD FTFGHLADKT DRLLMREFPM MNDGFDHLSP DMIIKTTSGV
     YNIVEFTNFR GDERGAFQAA MIKLAKYEVP CENRSQGRTV VLYVVSAYRA WCMVYLELER
     TLKQREMVYR YRLALSVMDE LRTLFPELSS TDEELGKTER ELPAMVSSIQ INWSVTESVF
     PPFSREMFDR FRSSPPDSEY ITRIVSRCLI NSQEKLINSS FFAEGNDKAL RFSKNAEECS
     LAVERALNQY RAEDNLRDLN DHKSTIQLPP WLSYHDVDGK DLCPLQGLDV RGDHPMCNLW
     REVVTSANLE EIERMHDDAA AELEFAFGSK GQARERNRYH RVHLNMGSDV LVYIAALGVN
     GKKHKADTLV QQMRDRSKQP FSPDHDVITY LNFSLHALVT CGQQMRTCTA LSLVIRDSVG
     SPEDSSAILV RKGFHEIITE HYKFMGSRIG HGCQMVSLIG AELSASVKQH VKPNYFVIKR
     LLGSGIFLLI KPTSSKSHIF VSFALSALAG PLISPLPGFS SPTKMLGILL VTDFVSYKLS
     KLTNLCKCVS LMESSFSFWA EAFGIQAGTL VGDFVPRSSD SAAMDASYMG KLSLLTLLED
     KAATEELQTI ARYIIMEGFV SPPEIPKPHK MTSKFPKVLR SELQVYLLNC LCRTIQRIAG
     EPFILKKKDG SISWGGMFNP FSGRPLLDMQ PLISCCYNGY FKNKEEETEP SSLSGMYKKI
     IELEHLRPQS DAFLGYKDPE LPRMHEFSVS YLKEACNHAK LVLRSLYGQN FMEQIDNQII
     RELSGLTLER LATLKATSNF NENWYVYKDV ADKNYTRDKL LVKMSKYASE GKSLAIQKFE
     DCMRQIESQG CMHICLFKKQ QHGGLREIYV MGAEERIVQS VVETIARSIG KFFASDTLCN
     PPNKVKIPET HGIRARKQCK GPVWTCATSD DARKWNQGHF VTKFALMLCE FTSPKWWPLI
     IRGCSMFTKK RMMMNLNYLK ILDGHRELDI RDDFVMDLFK AYHGEAEVPW AFKGKTYLET
     TTGMMQGILH YTSSLLHTIH QEYIRSLSFK IFNLKVAPEM SKSLVCDMMQ GSDDSSMLIS
     FPADDEKVLT RCKVAAAICF RMKKELGVYL AIYPSEKSTA NTDFVMEYNS EFYFHTQHVR
     PTIRWIAACC SLPEVETLVA RQEEASNLMT SVTEGGGSFS LAAIIQQAQC TLHYMLMGMG
     VSELFLEYKK AVLKWNDPGL GFFLLDNPYA CGLGGFRFNL FKAITRTDLQ KLYAFFMKKV
     KGSAARDWAD EDVTIPETCS VSPGGALILS SSLKWGSRKK FQKLRDRLNI PENWIELINE
     NPEVLYRAPR TGPEILLRIA EKVHSPGVVS SLSSGNAVCK VMASAVYFLS ATIFEDTGRP
     EFNFLEDSKY SLLQKMAAYS GFHGFNDMEP EDILFLFPNI EELESLDSIV YNKGEIDIIP
     RVNIRDATQT RVTIFNEQKN LRTSPEKLVS DKWFGTQKSR IGKTTFLAEW EKLKKIVKWL
     EDAPEATLAH TPLNNHIQVR NFFARMESKP RTVRITGAPV KKRSGVSKIA MVIRDHFSRM
     GHLRGVEDLA GFTRSVSAEI LKHFLFCILQ GPYSESYKLQ LIYRVLSSVS NVEIKESDGK
     TKTNLIGILQ RFLDGDHVVP IIEEMGAGTV GGFIKRQQSK VVQNKVVYYG VGIWRGFMDG
     YQVHLEIEND IGQPPRLRNV TTNCQSSPWD LSIPIRQWAE DMGVTNNQDY SSKSSRGARY
     WMHSFRMQGP SKPFGCPVYI IKGDMSDVIR LRKEEVEMKV RGSTLNLYTK HHSHQDLHIL
     SYTASDNDLS PGIFKSISDE GVAQALQLFE REPSNCWVRC ESVAPKFISA ILEICEGKRQ
     IKGINRTRLS EIVRICSESS LRSKVGSMFS FVANVEEAHD VDYDALMDLM IEDAKNNAFS
     HVVDCIELDV SGPYEMESFH GRSTLTCTPS TILIRTYTFY LTLHQTMISV QAFQVILDEG
     VLLIALVNNY LRGSKANCWV RCESVAPKFI SAILEICEGK RQIKGINRTR LSEIVEFVLN
     LPKIKSRIYV LICRQCHGAN FPPISVRRLM LEDIASVARR LIIVASFGS
//