RIR1_HHV11
ID RIR1_HHV11 Reviewed; 1137 AA.
AC P08543; B9VQG7; Q09I94;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 2.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=Ribonucleoside-diphosphate reductase large subunit {ECO:0000255|HAMAP-Rule:MF_04026};
DE Short=R1 {ECO:0000255|HAMAP-Rule:MF_04026};
DE EC=1.17.4.1 {ECO:0000255|HAMAP-Rule:MF_04026};
DE AltName: Full=Ribonucleotide reductase large subunit {ECO:0000255|HAMAP-Rule:MF_04026};
GN Name=RIR1 {ECO:0000255|HAMAP-Rule:MF_04026};
GN Synonyms=ICP6 {ECO:0000303|PubMed:25316792}; OrderedLocusNames=UL39;
OS Human herpesvirus 1 (strain 17) (HHV-1) (Human herpes simplex virus 1).
OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC Herpesvirales; Herpesviridae; Alphaherpesvirinae; Simplexvirus.
OX NCBI_TaxID=10299;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=2839594; DOI=10.1099/0022-1317-69-7-1531;
RA McGeoch D.J., Dalrymple M.A., Davison A.J., Dolan A., Frame M.C., McNab D.,
RA Perry L.J., Scott J.E., Taylor P.;
RT "The complete DNA sequence of the long unique region in the genome of
RT herpes simplex virus type 1.";
RL J. Gen. Virol. 69:1531-1574(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Isolate pYN1;
RX PubMed=2835765; DOI=10.1002/prot.340010411;
RA Nikas I., McLauchlan J., Davison A.J., Taylor W.R., Clements J.B.;
RT "Structural features of ribonucleotide reductase.";
RL Proteins 1:376-384(1986).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Nonneuroinvasive mutant HF10;
RX PubMed=17218138; DOI=10.1016/j.micinf.2006.10.019;
RA Ushijima Y., Luo C., Goshima F., Yamauchi Y., Kimura H., Nishiyama Y.;
RT "Determination and analysis of the DNA sequence of highly attenuated herpes
RT simplex virus type 1 mutant HF10, a potential oncolytic virus.";
RL Microbes Infect. 9:142-149(2007).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=17 syn+;
RA Cunningham C., Davison A.J.;
RT "Herpes simplex virus type 1 bacterial artificial chromosome.";
RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP REVIEW.
RX PubMed=18990579; DOI=10.1016/j.tibs.2008.09.008;
RA Lembo D., Brune W.;
RT "Tinkering with a viral ribonucleotide reductase.";
RL Trends Biochem. Sci. 34:25-32(2009).
RN [6]
RP INTERACTION WITH HOST RIPK3, AND MUTAGENESIS OF 73-VAL--GLY-76.
RX PubMed=25316792; DOI=10.1073/pnas.1412767111;
RA Wang X., Li Y., Liu S., Yu X., Li L., Shi C., He W., Li J., Xu L., Hu Z.,
RA Yu L., Yang Z., Chen Q., Ge L., Zhang Z., Zhou B., Jiang X., Chen S.,
RA He S.;
RT "Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus
RT 1 (HSV-1) protein ICP6 triggers host antiviral defense.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:15438-15443(2014).
RN [7]
RP FUNCTION, INTERACTION WITH HOST RIPK1; RIPK3 AND CASP8, AND MUTAGENESIS OF
RP 73-VAL--GLY-76.
RX PubMed=25674983; DOI=10.1016/j.chom.2015.01.003;
RA Guo H., Omoto S., Harris P.A., Finger J.N., Bertin J., Gough P.J.,
RA Kaiser W.J., Mocarski E.S.;
RT "Herpes simplex virus suppresses necroptosis in human cells.";
RL Cell Host Microbe 17:243-251(2015).
RN [8]
RP FUNCTION, AND MUTAGENESIS OF 73-VAL--GLY-76.
RX PubMed=30050136; DOI=10.1038/s41419-018-0868-3;
RA Guo H., Gilley R.P., Fisher A., Lane R., Landsteiner V.J., Ragan K.B.,
RA Dovey C.M., Carette J.E., Upton J.W., Mocarski E.S., Kaiser W.J.;
RT "Species-independent contribution of ZBP1/DAI/DLM-1-triggered necroptosis
RT in host defense against HSV1.";
RL Cell Death Dis. 9:816-816(2018).
RN [9]
RP FUNCTION, INTERACTION WITH HOST RIPK3 AND HOST ZBP1, DOMAIN, AND
RP MUTAGENESIS OF 73-VAL--GLY-76.
RX PubMed=33348174; DOI=10.1016/j.bpc.2020.106524;
RA Shanmugam N., Baker M.O.D.G., Sanz-Hernandez M., Sierecki E., Gambin Y.,
RA Steain M., Pham C.L.L., Sunde M.;
RT "Herpes simplex virus encoded ICP6 protein forms functional amyloid
RT assemblies with necroptosis-associated host proteins.";
RL Biophys. Chem. 269:106524-106524(2021).
CC -!- FUNCTION: Ribonucleoside-diphosphate reductase holoenzyme that provides
CC the precursors necessary for viral DNA synthesis (By similarity).
CC Allows virus growth in non-dividing cells, as well as reactivation from
CC latency in infected hosts. Catalyzes the biosynthesis of
CC deoxyribonucleotides from the corresponding ribonucleotides (By
CC similarity). Prevents host necroptosis by targeting host RIPK1 and
CC RIPK3, thereby hampering the formation of necroptotic RIPK1-RIPK3
CC complexes (PubMed:25674983, PubMed:30050136). Forms hetero-amyloid
CC structures with host proteins RIPK3 or ZBP1 which may prevent
CC RIPK3- and ZBP1-mediated necroptosis (PubMed:33348174). In addition,
CC inhibits extrinsic apoptosis by targeting host CASP8 (PubMed:25674983).
CC {ECO:0000255|HAMAP-Rule:MF_04026, ECO:0000269|PubMed:25674983,
CC ECO:0000269|PubMed:30050136, ECO:0000269|PubMed:33348174}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[thioredoxin]-disulfide + a 2'-deoxyribonucleoside 5'-
CC diphosphate + H2O = [thioredoxin]-dithiol + a ribonucleoside 5'-
CC diphosphate; Xref=Rhea:RHEA:23252, Rhea:RHEA-COMP:10698, Rhea:RHEA-
CC COMP:10700, ChEBI:CHEBI:15377, ChEBI:CHEBI:29950, ChEBI:CHEBI:50058,
CC ChEBI:CHEBI:57930, ChEBI:CHEBI:73316; EC=1.17.4.1;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_04026};
CC -!- PATHWAY: Genetic information processing; DNA replication.
CC {ECO:0000255|HAMAP-Rule:MF_04026}.
CC -!- SUBUNIT: Heterotetramer composed of a homodimer of the large subunit
CC (R1) and a homodimer of the small subunit (R2) (By similarity). Larger
CC multisubunit protein complex are also active, composed of (R1)n(R2)n
CC (By similarity). Self-assembles (via RIP homotypic interaction
CC motif/RHIM) into homomeric fibrillar amyloid structures
CC (PubMed:33348174). Interacts (via RHIM) with human RIPK1 (via RHIM)
CC (PubMed:25674983). Interacts (via RHIM) with human RIPK3 (via RHIM);
CC the interaction leads to heteromeric amyloid assemblies
CC (PubMed:25316792, PubMed:25674983, PubMed:33348174). Interacts (via
CC RHIM) with human ZBP1 (via RHIM); the interaction leads to heteromeric
CC amyloid assemblies (PubMed:33348174). Interacts (via C-terminus) with
CC host CASP8 (PubMed:25674983). {ECO:0000255|HAMAP-Rule:MF_04026,
CC ECO:0000269|PubMed:25316792, ECO:0000269|PubMed:25674983,
CC ECO:0000269|PubMed:33348174}.
CC -!- DOMAIN: The RIP homotypic interaction motif/RHIM drives self-assembly
CC into homomeric amyloid structures and mediates interaction with the
CC RHIM motif of host proteins RIPK3 and ZBP1 to form heteromeric amyloid
CC structures. {ECO:0000269|PubMed:33348174}.
CC -!- SIMILARITY: Belongs to the ribonucleoside diphosphate reductase large
CC chain family. {ECO:0000255|HAMAP-Rule:MF_04026}.
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DR EMBL; X14112; CAA32314.1; -; Genomic_DNA.
DR EMBL; M18410; AAA45805.1; -; Genomic_DNA.
DR EMBL; DQ889502; ABI63501.1; -; Genomic_DNA.
DR EMBL; FJ593289; ACM62262.1; -; Genomic_DNA.
DR PIR; A26536; WMBEB1.
DR RefSeq; YP_009137114.1; NC_001806.2.
DR SMR; P08543; -.
DR BioGRID; 971405; 3.
DR DIP; DIP-57653N; -.
DR IntAct; P08543; 5.
DR MINT; P08543; -.
DR BindingDB; P08543; -.
DR ChEMBL; CHEMBL3840; -.
DR DrugCentral; P08543; -.
DR PRIDE; P08543; -.
DR DNASU; 2703361; -.
DR GeneID; 2703361; -.
DR KEGG; vg:2703361; -.
DR Reactome; R-HSA-5213460; RIPK1-mediated regulated necrosis.
DR Reactome; R-HSA-9686347; Microbial modulation of RIPK1-mediated regulated necrosis.
DR UniPathway; UPA00326; -.
DR Proteomes; UP000009294; Genome.
DR Proteomes; UP000180652; Genome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-UniRule.
DR GO; GO:0004748; F:ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor; IEA:UniProtKB-UniRule.
DR GO; GO:0006260; P:DNA replication; IEA:UniProtKB-UniRule.
DR GO; GO:0019046; P:release from viral latency; IEA:UniProtKB-KW.
DR GO; GO:0039650; P:suppression by virus of host cysteine-type endopeptidase activity involved in apoptotic process; IEA:UniProtKB-KW.
DR HAMAP; MF_04026; HSV_RIR1; 1.
DR InterPro; IPR034717; HSV_RIR1.
DR InterPro; IPR013346; NrdE_NrdA.
DR InterPro; IPR000788; RNR_lg_C.
DR InterPro; IPR013509; RNR_lsu_N.
DR InterPro; IPR039718; Rrm1.
DR PANTHER; PTHR11573; PTHR11573; 1.
DR Pfam; PF02867; Ribonuc_red_lgC; 1.
DR Pfam; PF00317; Ribonuc_red_lgN; 1.
DR PRINTS; PR01183; RIBORDTASEM1.
DR TIGRFAMs; TIGR02506; NrdE_NrdA; 1.
DR PROSITE; PS00089; RIBORED_LARGE; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Disulfide bond; DNA replication; Early protein;
KW Host-virus interaction; Inhibition of host caspases by virus;
KW Modulation of host cell apoptosis by virus; Nucleotide-binding;
KW Oxidoreductase; Reference proteome; Viral latency;
KW Viral reactivation from latency.
FT CHAIN 1..1137
FT /note="Ribonucleoside-diphosphate reductase large subunit"
FT /id="PRO_0000187236"
FT REGION 1..32
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 124..159
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 173..315
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 64..84
FT /note="RIP homotypic interaction motif (RHIM)"
FT /evidence="ECO:0000269|PubMed:25316792"
FT COMPBIAS 128..142
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 791
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT ACT_SITE 793
FT /note="Cysteine radical intermediate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT ACT_SITE 795
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT BINDING 566
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT BINDING 581..582
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT BINDING 612
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT BINDING 791..795
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT BINDING 968..972
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT SITE 582
FT /note="Important for hydrogen atom transfer"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT SITE 808
FT /note="Important for hydrogen atom transfer"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT SITE 1111
FT /note="Important for electron transfer"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT SITE 1112
FT /note="Important for electron transfer"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT SITE 1132
FT /note="Interacts with thioredoxin/glutaredoxin"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT SITE 1135
FT /note="Interacts with thioredoxin/glutaredoxin"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT DISULFID 582..808
FT /note="Redox-active"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT VARIANT 70
FT /note="N -> S (in strain: Nonneuroinvasive mutant HF10, 17
FT syn+ and Isolate pYN1)"
FT VARIANT 1133
FT /note="M -> T (in strain: Nonneuroinvasive mutant HF10)"
FT MUTAGEN 73..76
FT /note="VQCG->AAAA: No homomeric amyloid formation.
FT Abolished interaction with human RIPK3. Decreased
FT interaction with human ZBP1. Loss of ability to prevent
FT necroptosis."
FT /evidence="ECO:0000269|PubMed:25316792,
FT ECO:0000269|PubMed:25674983, ECO:0000269|PubMed:30050136,
FT ECO:0000269|PubMed:33348174"
FT CONFLICT 1034
FT /note="A -> P (in Ref. 2; AAA45805)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1137 AA; 124051 MW; 8A3777F4C22D8F85 CRC64;
MASRPAASSP VEARAPVGGQ EAGGPSAATQ GEAAGAPLAH GHHVYCQRVN GVMVLSDKTP
GSASYRISDN NFVQCGSNCT MIIDGDVVRG RPQDPGAAAS PAPFVAVTNI GAGSDGGTAV
VAFGGTPRRS AGTSTGTQTA DVPTEALGGP PPPPRFTLGG GCCSCRDTRR RSAVFGGEGD
PVGPAEFVSD DRSSDSDSDD SEDTDSETLS HASSDVSGGA TYDDALDSDS SSDDSLQIDG
PVCRPWSNDT APLDVCPGTP GPGADAGGPS AVDPHAPTPE AGAGLAADPA VARDDAEGLS
DPRPRLGTGT AYPVPLELTP ENAEAVARFL GDAVNREPAL MLEYFCRCAR EETKRVPPRT
FGSPPRLTED DFGLLNYALV EMQRLCLDVP PVPPNAYMPY YLREYVTRLV NGFKPLVSRS
ARLYRILGVL VHLRIRTREA SFEEWLRSKE VALDFGLTER LREHEAQLVI LAQALDHYDC
LIHSTPHTLV ERGLQSALKY EEFYLKRFGG HYMESVFQMY TRIAGFLACR ATRGMRHIAL
GREGSWWEMF KFFFHRLYDH QIVPSTPAML NLGTRNYYTS SCYLVNPQAT TNKATLRAIT
SNVSAILARN GGIGLCVQAF NDSGPGTASV MPALKVLDSL VAAHNKESAR PTGACVYLEP
WHTDVRAVLR MKGVLAGEEA QRCDNIFSAL WMPDLFFKRL IRHLDGEKNV TWTLFDRDTS
MSLADFHGEE FEKLYQHLEV MGFGEQIPIQ ELAYGIVRSA ATTGSPFVMF KDAVNRHYIY
DTQGAAIAGS NLCTEIVHPA SKRSSGVCNL GSVNLARCVS RQTFDFGRLR DAVQACVLMV
NIMIDSTLQP TPQCTRGNDN LRSMGIGMQG LHTACLKLGL DLESAEFQDL NKHIAEVMLL
SAMKTSNALC VRGARPFNHF KRSMYRAGRF HWERFPDARP RYEGEWEMLR QSMMKHGLRN
SQFVALMPTA ASAQISDVSE GFAPLFTNLF SKVTRDGETL RPNTLLLKEL ERTFSGKRLL
EVMDSLDAKQ WSVAQALPCL EPTHPLRRFK TAFDYDQKLL IDLCADRAPY VDHSQSMTLY
VTEKADGTLP ASTLVRLLVH AYKRGLKTGM YYCKVRKATN SGVFGGDDNI VCMSCAL
