L_HTRV
ID L_HTRV Reviewed; 2084 AA.
AC J3TRD1;
DT 03-AUG-2022, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2012, sequence version 1.
DT 03-AUG-2022, entry version 37.
DE RecName: Full=RNA-directed RNA polymerase L;
DE Short=Protein L;
DE EC=2.7.7.48 {ECO:0000250|UniProtKB:P33453};
DE AltName: Full=Large structural protein;
DE AltName: Full=Replicase {ECO:0000305};
DE AltName: Full=Transcriptase {ECO:0000305};
DE Includes:
DE RecName: Full=cap-snatching endonuclease;
DE EC=3.1.-.- {ECO:0000269|PubMed:31914382};
GN Name=L;
OS Heartland virus (HTRV).
OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC Ellioviricetes; Bunyavirales; Phenuiviridae; Bandavirus;
OC Heartland bandavirus.
OX NCBI_TaxID=1216928;
OH NCBI_TaxID=999462; Alces americanus (American moose).
OH NCBI_TaxID=6943; Amblyomma americanum (Lone star tick).
OH NCBI_TaxID=9614; Canis latrans (Coyote).
OH NCBI_TaxID=9267; Didelphis virginiana (North American opossum) (Didelphis marsupialis virginiana).
OH NCBI_TaxID=9796; Equus caballus (Horse).
OH NCBI_TaxID=9606; Homo sapiens (Human).
OH NCBI_TaxID=9874; Odocoileus virginianus (White-tailed deer).
OH NCBI_TaxID=9654; Procyon lotor (Raccoon).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC STRAIN=Isolate Human/United States/1/2009, and
RC Isolate Human/United States/2/2009;
RA McMullan L.K., Folk S.M., Kelly A.J., MacNeil A., Goldsmith C.S.,
RA Metcalfe M.G., Batten B.C., Albarino C.G., Zaki S.R., Rollin P.E.,
RA Nicholson W.L., Nichol S.T.;
RT "A newly discovered phlebovirus associated with severe febrile illness
RT following tick bite in two patients in Missouri.";
RL N. Engl. J. Med. 367:834-841(2012).
RN [2]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND FUNCTION.
RX PubMed=31914382; DOI=10.1016/j.celrep.2019.12.020;
RA Wang W., Shin W.J., Zhang B., Choi Y., Yoo J.S., Zimmerman M.I.,
RA Frederick T.E., Bowman G.R., Gross M.L., Leung D.W., Jung J.U.,
RA Amarasinghe G.K.;
RT "The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target.";
RL Cell Rep. 30:153-163.e5(2020).
RN [3]
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 [4]
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).
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 (By similarity). 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:31914382). 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:0000250|UniProtKB:P27316,
CC ECO:0000269|PubMed:31914382}.
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 -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:P27316};
CC Note=For endonuclease activity. Binds 2 Mn(2+) ions in the active site
CC (By similarity). The divalent metal ions are crucial for catalytic
CC activity (PubMed:31948728). {ECO:0000250|UniProtKB:P27316,
CC ECO:0000269|PubMed:31948728};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P27316};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:P27316};
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:0000250|UniProtKB:P27316};
CC -!- ACTIVITY REGULATION: Inhibited by Baloxavir acid (BXA).
CC {ECO:0000269|PubMed:31914382}.
CC -!- SUBUNIT: Homomultimer (By similarity). Interacts with glycoprotein N;
CC this interaction allows efficient polymerase packaging into virus
CC particles (By similarity). Interacts with nucleoprotein N (By
CC similarity). {ECO:0000250|UniProtKB:P27316}.
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; JX005846; AFP33395.1; -; Genomic_RNA.
DR RefSeq; YP_009047242.1; NC_024495.1.
DR GeneID; 19893500; -.
DR KEGG; vg:19893500; -.
DR Proteomes; UP000203778; Genome.
DR GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IEA:UniProtKB-EC.
DR GO; GO:0006351; P:transcription, DNA-templated; IEA:InterPro.
DR GO; GO:0039694; P:viral RNA genome replication; IEA:InterPro.
DR InterPro; IPR022531; DUF3770.
DR InterPro; IPR029124; L_protein_N.
DR InterPro; IPR007099; RNA-dir_pol_NSvirus.
DR InterPro; IPR007322; RNA_pol_bunyavir.
DR Pfam; PF04196; Bunya_RdRp; 1.
DR Pfam; PF12603; DUF3770; 1.
DR Pfam; PF15518; L_protein_N; 1.
DR PROSITE; PS50525; RDRP_SSRNA_NEG_SEG; 1.
PE 1: Evidence at protein level;
KW Host endoplasmic reticulum; Host Golgi apparatus; Hydrolase; Magnesium;
KW Manganese; Metal-binding; Nucleotide-binding; Nucleotidyltransferase;
KW RNA-directed RNA polymerase; Transferase; Viral RNA replication; Virion.
FT CHAIN 1..2084
FT /note="RNA-directed RNA polymerase L"
FT /id="PRO_0000456060"
FT DOMAIN 969..1172
FT /note="RdRp catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT REGION 20..221
FT /note="Endonuclease"
FT /evidence="ECO:0000250|UniProtKB:A5HC98"
FT REGION 1696..1810
FT /note="Cap-binding"
FT /evidence="ECO:0000250|UniProtKB:A5HC98"
FT ACT_SITE 145
FT /note="For endonuclease activity"
FT /evidence="ECO:0000250|UniProtKB:I0DF35"
FT BINDING 80
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:A5HC98"
FT BINDING 112
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:A5HC98"
FT BINDING 112
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:A5HC98"
FT BINDING 126
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:A5HC98"
FT BINDING 1127
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic; for RdRp activity"
FT /evidence="ECO:0000250|UniProtKB:I0DF35"
FT SITE 1703
FT /note="Interaction with the cap substrate"
FT /evidence="ECO:0000250|UniProtKB:A2SZS3"
FT SITE 1707
FT /note="Interaction with the cap substrate"
FT /evidence="ECO:0000250|UniProtKB:A2SZS3"
FT SITE 1719
FT /note="Interaction with the cap substrate"
FT /evidence="ECO:0000250|UniProtKB:A2SZS3"
FT SITE 1772
FT /note="Interaction with the cap substrate"
FT /evidence="ECO:0000250|UniProtKB:A2SZS3"
SQ SEQUENCE 2084 AA; 236364 MW; E4070623FEBE9533 CRC64;
MNLEALCSRV LSERGLSTGE PGVYDQIFER PGLPNLEVTV DSTGVVVDVG AIPDSASQLG
SSINAGVLTI PLSEAYKINH DFTFSGLTKT TDRKLSEVFP LVHDGSDSMT PDVIHTRLDG
TVVVIEFTTT RSTNMGGLEA AYRSKLEKYR DPLNRRTDIM PDASIYFGII VVSASGVLTN
MPLTQDEAEE LMFRFCVANE IYSQARAMDA EVELQKSEEE YEAISRARAF FTLFDYDDGK
LSEAFPNSDI EMLRRFLSQP VDTSFVTTTL KEKEQEAYKR MCEEHYLKSG MSTKERLEAN
RSDAIDKTRA LMERLHNMSS KELHSNKSTV KLPPWVVKPS DRTLDVKTDT GSGELLNHGP
YGELWSRCFL EIVLGNVEGV ISSPEKELEI AISDDPEADT PKAAKIKYHR FRPELSLESK
HEFSLQGIEG KRWKHSARNV LKDEMSHKTM SPFVDVSNIE EFLIMNNLLN DTSFNREGLQ
ETINLLLEKA TEMHQNGLST ALNDSFKRNF NTNVVQWSMW VSCLAQELAS ALKQHCKPGE
FIIKKLMHWP IFVIIKPTKS SSHIFYSLAI KKANIKRRLI GDVFTDTIDA GEWEFSEFKS
LKTCKLTNLI NLPCTMLNSI AFWREKMGVA PWISRKACSE LREQVAITFL MSLEDKSTTE
ELVTLTRYSQ MEGFVSPPLL PKPQKMVEKL EVPLRTKLQV FLFRRHLDAI VRVAASPFPI
VARDGRVEWT GTFNAITGRS TGLENMVNNW YIGYYKNKEE STELNALGEM YKKIVEIEAE
KPTSSEYLGW GDTSSPKRHE FSRSFLKSAC ISLEKEIEMR HGKSWKQSLE ERVLKELGSK
NLLDLATMKA TSNFSKEWEA FSEVRTKEYH RSKLLEKMAE LIEHGLMWYV DAAGHAWKAV
LDDKCMRICL FKKNQHGGLR EIYVTNANAR LVQFGVETMA RCVCELSPHE TIANPRLKSS
IIENHGLKSA RQLGQGTINV NSSNDAKKWS QGHYTTKLAM VLCWFMPAKF HRFIWAGISM
FRCKKMMMDL RFLEKLSTKA NQKTDDDFRK DLAGAFHGNV EVPWMTQGAT YLQTETGMMQ
GILHFTSSLL HSCVQSFYKA YFLSRLKEGI AGRTIKAAID VLEGSDDSAI MISLKPASDN
EEAMARFLTA NLLYSVRVIN PLFGIYSSEK STVNTLFCVE YNSEFHFHKH LVRPTIRWVA
ASHQISESEA LASRQEDYAN LLTQCLEGGS SFSLTYLIQC AQLVHHYMLL GLCLHPLFGT
FVGMLIEDPD PALGFFIMDN PAFAGGAGFR FNLWRSCKFT NLGKKYAFFF NEIQGKTKGD
ADYRALDATT GGTLSHSVMT YWGDRRKYQH LLDRMGLPKD WVERIDENPS ILYRRPENKQ
ELILRLAEKV HSPGVTSSFS KGHVVPRVVA AGVYLLSRHC FRYTASIHGR GASQKASLIK
LLVMSSTSAE RNQGRLNPNQ ERMLFPQVQE YERVLTLLDE VTALTGKFVV RERNIVKSRV
ELFQEPVDLR CKAENLIAEM WFGLKRTKLG PRLLKEEWDK LRASFSWLST DHKETLDVGP
FLSHVQFRNF IAHVDAKSRS VRLLGAPVKK SGGVTTVSQV VKSNFFPGFI LDSSESLDDQ
ERVEGVSILK HILFMTLNGP YTDEQKKAMV LETFQYFALP HAAEVVKRSR SLTLCLMKNF
IEQRGGSILD QIEKAQSGTV GGFSKPQKPY RKQSGGIGYK GKGVWSGIME NTNVQILIDG
DGSSNWIEEI RLSSESRLFD VIESVRRLCD DINVNNRVTS SFRGHCMVRL SNFKVKPASR
VEGCPVRLMP SSFRIKELQN PDEVFLRVRG DILNLSILLQ EDRVMNLLSY RARDTDISES
AASYLWMNRT DFSFGKKEPS CSWMCLKTLD SWAWNQAARV LERNIKTPGI DNTAMGNIFK
DCLESSLRKQ GLLRSRIAEM VERHVIPLTS QELVDILEED VDFSEMMQSD IMEGDLDIDI
LMEGSPMLWA AEVEEMGEAM VILSQSGKYY HLKLMDQAAT TLSTILGKDG CRLLLGRPTG
RSNLREQVKP YLTLLQIREG DVNWVSEYKD DTRGLDEDSA EMWG
