L_LASV
ID L_LASV Reviewed; 2219 AA.
AC Q6GWS6;
DT 03-AUG-2022, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 87.
DE RecName: Full=RNA-directed RNA polymerase L {ECO:0000255|HAMAP-Rule:MF_04086};
DE Short=Protein L {ECO:0000255|HAMAP-Rule:MF_04086};
DE EC=2.7.7.48 {ECO:0000255|HAMAP-Rule:MF_04086};
DE AltName: Full=Large structural protein {ECO:0000255|HAMAP-Rule:MF_04086};
DE AltName: Full=Replicase {ECO:0000255|HAMAP-Rule:MF_04086};
DE AltName: Full=Transcriptase {ECO:0000255|HAMAP-Rule:MF_04086};
DE Includes:
DE RecName: Full=cap-snatching endonuclease {ECO:0000255|HAMAP-Rule:MF_04086};
DE EC=3.1.-.- {ECO:0000255|HAMAP-Rule:MF_04086, ECO:0000269|PubMed:27304209};
GN Name=L {ECO:0000255|HAMAP-Rule:MF_04086};
GN ORFNames=AVI29_00002 {ECO:0000312|EMBL:AMZ00375.1};
OS Lassa virus (LASV) (Lassa mammarenavirus).
OC Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC Ellioviricetes; Bunyavirales; Arenaviridae; Mammarenavirus.
OX NCBI_TaxID=11620;
OH NCBI_TaxID=9606; Homo sapiens (Human).
OH NCBI_TaxID=10112; Mastomys natalensis (African soft-furred rat) (Praomys natalensis).
OH NCBI_TaxID=10114; Rattus.
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC STRAIN=Macenta {ECO:0000312|EMBL:AAT48998.1};
RA Hajjaj A., Chain P.S.G., Do L.H., Smith K.L., Imbro P.M., Malfatti S.A.;
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC STRAIN=Macenta {ECO:0000312|EMBL:AAT48998.1};
RA Jahrling P.B., Geisbert J., Ibrahim M.S.;
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC STRAIN=GUINEA Z-185a {ECO:0000312|EMBL:AMZ00375.1};
RA Rossi S.L., Guerbois M., Forrester N.L., Ksiazek T., Lin D., Hari K.,
RA Weaver S.C.;
RL Submitted (MAR-2016) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RC STRAIN=IRF0185 {ECO:0000312|EMBL:APT69533.1}, and
RC IRF0194 {ECO:0000312|EMBL:APT69523.1};
RA Mah S.A., Swanson W.J., Moy G.W., Vacquier V.D.;
RL Submitted (JAN-2017) to the EMBL/GenBank/DDBJ databases.
RN [5]
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 [6]
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 [7] {ECO:0007744|PDB:5IZH, ECO:0007744|PDB:5J1N, ECO:0007744|PDB:5J1P}
RP X-RAY CRYSTALLOGRAPHY (1.09 ANGSTROMS) OF 1-179 IN COMPLEX WITH MANGANESE,
RP CATALYTIC ACTIVITY, COFACTOR, MUTAGENESIS OF GLU-51; ASP-66; ASP-89;
RP GLU-102 AND LYS-115, AND ACTIVE SITE.
RX PubMed=27304209; DOI=10.1371/journal.ppat.1005636;
RA Reguera J., Gerlach P., Rosenthal M., Gaudon S., Coscia F., Guenther S.,
RA Cusack S.;
RT "Comparative Structural and Functional Analysis of Bunyavirus and
RT Arenavirus Cap-Snatching Endonucleases.";
RL PLoS Pathog. 12:e1005636-e1005636(2016).
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. During transcription, synthesizes subgenomic
CC RNAs and assures their capping by a cap-snatching mechanism, which
CC involves the endonuclease activity cleaving the host capped pre-mRNAs.
CC These short capped RNAs are then used as primers for viral
CC transcription. The 3'-end of subgenomic mRNAs molecules are
CC heterogeneous and not polyadenylated. The replicase function is to
CC direct synthesis of antigenomic and genomic RNA which are encapsidated
CC and non capped. As a consequence of the use of the same enzyme for both
CC transcription and replication, these mechanisms need to be well
CC coordinated. These processes may be regulated by proteins N and Z in a
CC dose-dependent manner. {ECO:0000255|HAMAP-Rule:MF_04086}.
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|HAMAP-Rule:MF_04086};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_04086,
CC ECO:0000269|PubMed:27304209};
CC Note=For endonuclease activity. Binds 2 Mn(2+) ions in the active site.
CC The divalent metal ions are crucial for catalytic activity
CC (PubMed:27304209). {ECO:0000255|HAMAP-Rule:MF_04086,
CC ECO:0000269|PubMed:27304209};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:A2SZS3,
CC ECO:0000255|HAMAP-Rule:MF_04086};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:A2SZS3,
CC ECO:0000255|HAMAP-Rule:MF_04086, ECO:0000269|PubMed:27304209};
CC Note=For polymerase activity. {ECO:0000250|UniProtKB:A2SZS3,
CC ECO:0000255|HAMAP-Rule:MF_04086};
CC -!- SUBUNIT: Homomultimer; the oligomeric structure is essential for the
CC polymerase activity. Interacts with nucleoprotein N. Interacts with
CC protein Z; this interaction inhibits viral transcription and
CC replication. {ECO:0000255|HAMAP-Rule:MF_04086}.
CC -!- SUBCELLULAR LOCATION: Virion {ECO:0000255|HAMAP-Rule:MF_04086}. Host
CC cytoplasm {ECO:0000255|HAMAP-Rule:MF_04086}.
CC -!- DOMAIN: The N-terminus contains the endonuclease activity (endoN). The
CC central region contains the RdRp activity. {ECO:0000255|HAMAP-
CC Rule:MF_04086}.
CC -!- MISCELLANEOUS: Classified as His(-) endonuclease since it does not have
CC a histidine upstream of the active site that coordinates the first
CC cation. His(-) endonucleases display very low activity in vitro,
CC although they are clearly active in vivo. {ECO:0000255|HAMAP-
CC Rule:MF_04086, ECO:0000269|PubMed:27304209}.
CC -!- SIMILARITY: Belongs to the Bunyavirales RNA polymerase family.
CC {ECO:0000255|HAMAP-Rule:MF_04086}.
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DR EMBL; AY628200; AAT48998.1; -; Genomic_RNA.
DR EMBL; KU978809; AMZ00375.1; -; Genomic_RNA.
DR EMBL; KY425626; APT69523.1; -; Genomic_RNA.
DR EMBL; KY425628; APT69533.1; -; Genomic_RNA.
DR PDB; 5IZH; X-ray; 1.85 A; A/B=1-170.
DR PDB; 5J1N; X-ray; 1.09 A; A=1-174.
DR PDB; 5J1P; X-ray; 2.36 A; A=1-174.
DR PDBsum; 5IZH; -.
DR PDBsum; 5J1N; -.
DR PDBsum; 5J1P; -.
DR SMR; Q6GWS6; -.
DR Proteomes; UP000157272; Genome.
DR GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0044423; C:virion component; IEA:UniProtKB-UniRule.
DR GO; GO:0016787; F:hydrolase activity; IEA:UniProtKB-KW.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-UniRule.
DR GO; GO:0003968; F:RNA-directed 5'-3' RNA polymerase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0075526; P:cap snatching; IEA:UniProtKB-UniRule.
DR GO; GO:0039689; P:negative stranded viral RNA replication; IEA:UniProtKB-UniRule.
DR HAMAP; MF_04086; ARENA_L; 1.
DR InterPro; IPR026382; CapSnatchArena.
DR InterPro; IPR007099; RNA-dir_pol_NSvirus.
DR InterPro; IPR010453; RNA_pol_arenavir.
DR Pfam; PF06317; Arena_RNA_pol; 1.
DR Pfam; PF17296; ArenaCapSnatch; 1.
DR PIRSF; PIRSF000836; L_ArenaV; 1.
DR PROSITE; PS00591; GH10_1; 1.
DR PROSITE; PS50525; RDRP_SSRNA_NEG_SEG; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cap snatching; Host cytoplasm; Hydrolase; Magnesium;
KW Metal-binding; Nucleotide-binding; Nucleotidyltransferase;
KW RNA-directed RNA polymerase; Transferase; Viral RNA replication; Virion.
FT CHAIN 1..2219
FT /note="RNA-directed RNA polymerase L"
FT /id="PRO_0000456061"
FT DOMAIN 1177..1373
FT /note="RdRp catalytic"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086"
FT REGION 26..289
FT /note="Endonuclease"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086"
FT ACT_SITE 115
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086,
FT ECO:0000305|PubMed:27304209"
FT BINDING 51
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086,
FT ECO:0000269|PubMed:27304209"
FT BINDING 89
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086,
FT ECO:0000269|PubMed:27304209"
FT BINDING 89
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086,
FT ECO:0000269|PubMed:27304209"
FT BINDING 102
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086,
FT ECO:0000269|PubMed:27304209"
FT BINDING 1335
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic; for RdRp activity"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04086"
FT MUTAGEN 51
FT /note="E->A: Loss of endonuclease stability."
FT /evidence="ECO:0000269|PubMed:27304209"
FT MUTAGEN 51
FT /note="E->H: No improvement of endonuclease activity in
FT vitro."
FT /evidence="ECO:0000269|PubMed:27304209"
FT MUTAGEN 66
FT /note="D->A: No effect on endonuclease stability."
FT /evidence="ECO:0000269|PubMed:27304209"
FT MUTAGEN 89
FT /note="D->A: Complete loss of endonuclease stability.
FT Complete loss of Mn(2+) binding."
FT /evidence="ECO:0000269|PubMed:27304209"
FT MUTAGEN 102
FT /note="E->A: Loss of endonuclease stability."
FT /evidence="ECO:0000269|PubMed:27304209"
FT MUTAGEN 115
FT /note="K->A: No effect on endonuclease stability."
FT /evidence="ECO:0000269|PubMed:27304209"
SQ SEQUENCE 2219 AA; 254023 MW; 9DDC574F07AA08D5 CRC64;
MEEDIACVKD LVSKYLADNE RLSRQKLAFL VQTEPRMLLM EGLKLLSLCI EIDSCNANGC
EHNSEDKSVE RILHDHGILT PSLCFVVPDG YKLTGNVLIL LECFVRSSPA NFEQKYIEDF
KKLEQLKEDL KTVNISLIPL IDGRTSFYNE QIPDWVNDKL RDTLFSLLRY AQESNSLFEE
SEYSRLCESL SMTSGRLSGV ESLNVLLDNR SNHYEEVIAS CHQGINNKLT AHEVKLQIEE
EYQVFRNRLR KGEIESQFLK VEKSRLLNEF NDLYMDKVST TEDDVEYLIH QFKRASPILR
FLYANVGKEA NEKSDQTIKE CQMQYWRSFL NKVKSLRILN TRRKLLLIFD VLILLASKYD
QMKYKSLRGW LGSCFISVND RLVSLESTKR DLKKWVERRQ QAEMSKTMQS SQCSNKNQIL
NSMLQKTILK ATTALKDVGI SVDQYKVDME IMCPNCYDSV MDFDVSGITP TISYQRSEEE
KFPYIMGSVE LLETVDLERL SSLSLALVNS MKTSSTVKLR QNEFGPARYQ VVRCREAYCQ
EFSLGDTEFQ LVYQKTGECS KCYAINDNRV GEICSFYADP KRYFPAIFSA EVLQATVGTM
ISWIEDCSEL EGQLHNIRSL TKMILVLILT HPSKRSQKLL QNLRYFIMAY VSDFYHKDLI
DKIREELITD TEFLLYRLVR ALMGLILSEN VKSMMTNRFK FILNISYMCH FITKETPDRL
TDQIKCFEKF LEPKVKFGHV SINPADIATE EELDDMIYNA KKFLNKDGCT SAKGPDYKRP
GVSKKFLSLL TSSFNNGSLF KEKEVKKDIK DPLITSGCAT ALDLASNKSV VVNKYTDGSR
VLNYDFNKLT ALAVSQLTEV FSRKGKHLLN KQDYEYKVQQ AMSNLVLGSR QHKTDADEAD
LDEILLDGGA SVYFDQLRET VEKIVDQYRE PVKPGSGPDD DGQPSVNDLD EVISNKFHIR
LIKGELSNHM VEDFDHDVLP DKFYKEFCDA VYENDKLKER YFYCGHMSQC PIGELTKAVT
TRTYFDHEYF QCFKSILLKM NANTLMGRYT HYKSRNLNFK FDMGKLSDDV RISERESNSE
ALSKALSLTN CTTAMLKNLC FYSQESPQSY NSVGPDTGRL KFSLSYKEQV GGNRELYIGD
LRTKMFTRLI EDYFEALSLQ LSGSCLNNEK EFENAILSMK LNVSLAHVSY SMDHSKWGPM
MCPFLFLAVL QNLIFLSKDL QADIKGRDYL STLLMWHMHK MVEIPFNVVS AMMKSFIKAQ
LGLRKKTTQS ITEDFFYSSF QVGVVPSHVS SILDMGQGIL HNTSDFYALI SERFINYAIS
CICGGVVDAY TSSDDQISLF DQTLTELLQR DPDEFKTLMD FHYYMSDQLN KFVSPKSVIG
RFVAEFKSRF FVWGDEVPLL TKFVAAALHN IKCKEPHQLA ETIDTIIDQS VANGVPVHLC
NLIQMRTLSL LQYARYPIDP FLLNCETDVR DWVDGNRSYR IMRQIEGLIP DACSKIRSML
RKLYNRLKTG QLHEEFTTNY LSSEHLSSLR NLCELLGVEP PSESDLEFSW LNLAAHHPLR
MVLRQKIIYS GAVNLDDEKV PTIVKTIQNK LSSTFTRGAQ KLLSEAINKS AFQSSIASGF
VGLCRTLGSK CVRGPNKENL YIKSIQSLIS GTQGIELLTN SYGVQYWRVP LNLRSENESV
VSYFRPLLWD YMCISLSTAI ELGAWVLGEP KMTKALEFFK HNPCDYFPLK PTASKLLEDR
IGLNHIIHSL RRLYPSVFEK HILPFMSDLA STKMKWSPRI KFLDLCVALD VSCEALSLVS
HIVKWKREEH YIVLSSELRL SHTRTHEPMV EERVVSTSDA VDNFMRQIYF ESYVRPFVAT
TRTLGSFTWF PHKTSIPEGE GLQRLGPFSS FVEKVIHKGV ERPMFKHDLM MGYAWIDFDI
EPARLNQNQL IASGLVSTKF DSLEDFFDAV ASLPSGSTRL SQTVRFRIKS QDASFKETFA
IHLDYTGSMN QQTKYLVHDV TVMYSGAVNP CVLLDCWRLV MSGSTFKGKS AWYVDTEVIN
EFLIDTNQLG HVTPVEIVVD AEKLQFTEYD FVLVGPCTEP APLVVHKGGL WECGKKLASF
TPVIQDQDLE MFVKEVGDTS SDLLTEALSA MMLDRLGLKM QWSGVDIVST LKAAVPQSME
ILGAVLEAVD NWVEFKGYAL CYSKSRRRIM VQSSGGKLRL KGRTCEELIE RDEHIEDIE
