RIR1_MUHVS
ID RIR1_MUHVS Reviewed; 1174 AA.
AC Q06A28;
DT 27-JUL-2011, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 59.
DE RecName: Full=Ribonucleoside-diphosphate reductase large subunit-like protein {ECO:0000255|HAMAP-Rule:MF_04027};
DE AltName: Full=Viral inhibitor of RIP activation;
DE Contains:
DE RecName: Full=N-terminal peptide;
DE Contains:
DE RecName: Full=116 kDa peptide;
GN Name=RIR1 {ECO:0000255|HAMAP-Rule:MF_04027}; Synonyms=M45, m45.1;
OS Murid herpesvirus 1 (strain Smith) (MuHV-1) (Mouse cytomegalovirus).
OC Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC Herpesvirales; Herpesviridae; Betaherpesvirinae; Muromegalovirus.
OX NCBI_TaxID=10367;
OH NCBI_TaxID=10090; Mus musculus (Mouse).
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=8971012; DOI=10.1128/jvi.70.12.8833-8849.1996;
RA Rawlinson W.D., Farrell H.E., Barrell B.G.;
RT "Analysis of the complete DNA sequence of murine cytomegalovirus.";
RL J. Virol. 70:8833-8849(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RX PubMed=11209080; DOI=10.1126/science.291.5502.303;
RA Brune W., Menard C., Heesemann J., Koszinowski U.H.;
RT "A ribonucleotide reductase homolog of cytomegalovirus and endothelial cell
RT tropism.";
RL Science 291:303-305(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND INTERACTION WITH MOUSE
RP RIPK1.
RX PubMed=18287053; DOI=10.1073/pnas.0800168105;
RA Mack C., Sickmann A., Lembo D., Brune W.;
RT "Inhibition of proinflammatory and innate immune signaling pathways by a
RT cytomegalovirus RIP1-interacting protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:3094-3099(2008).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=20015993; DOI=10.1128/jvi.02142-09;
RA Cheng T.P., Valentine M.C., Gao J., Pingel J.T., Yokoyama W.M.;
RT "Stability of murine cytomegalovirus genome after in vitro and in vivo
RT passage.";
RL J. Virol. 84:2623-2628(2010).
RN [5]
RP PROTEIN SEQUENCE OF 278-284, PROTEOLYTIC CLEAVAGE, LACK OF
RP RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=15047841; DOI=10.1128/jvi.78.8.4278-4288.2004;
RA Lembo D., Donalisio M., Hofer A., Cornaglia M., Brune W., Koszinowski U.,
RA Thelander L., Landolfo S.;
RT "The ribonucleotide reductase R1 homolog of murine cytomegalovirus is not a
RT functional enzyme subunit but is required for pathogenesis.";
RL J. Virol. 78:4278-4288(2004).
RN [6]
RP FUNCTION, AND INTERACTION WITH MOUSE RIPK1 AND RIPK3.
RX PubMed=18442983; DOI=10.1074/jbc.c800051200;
RA Upton J.W., Kaiser W.J., Mocarski E.S.;
RT "Cytomegalovirus M45 cell death suppression requires receptor-interacting
RT protein (RIP) homotypic interaction motif (RHIM)-dependent interaction with
RT RIP1.";
RL J. Biol. Chem. 283:16966-16970(2008).
RN [7]
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 [8]
RP FUNCTION, AND INTERACTION WITH MOUSE ZBP1.
RX PubMed=19590578; DOI=10.1038/embor.2009.109;
RA Rebsamen M., Heinz L.X., Meylan E., Michallet M.C., Schroder K.,
RA Hofmann K., Vazquez J., Benedict C.A., Tschopp J.;
RT "DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs
RT to activate NF-kappaB.";
RL EMBO Rep. 10:916-922(2009).
RN [9]
RP FUNCTION, INTERACTION WITH MOUSE RIPK3, AND MUTAGENESIS OF 61-ILE--GLY-64.
RX PubMed=20413098; DOI=10.1016/j.chom.2010.03.006;
RA Upton J.W., Kaiser W.J., Mocarski E.S.;
RT "Virus inhibition of RIP3-dependent necrosis.";
RL Cell Host Microbe 7:302-313(2010).
RN [10]
RP FUNCTION, AND MUTAGENESIS OF 61-ILE--GLY-64.
RX PubMed=28716805; DOI=10.15252/embj.201796476;
RA Maelfait J., Liverpool L., Bridgeman A., Ragan K.B., Upton J.W.,
RA Rehwinkel J.;
RT "Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis.";
RL EMBO J. 36:2529-2543(2017).
RN [11]
RP FUNCTION, INTERACTION WITH MOUSE RIPK1; RIPK3 AND ZBP1, DOMAIN, AND
RP SUBUNIT.
RX PubMed=30498077; DOI=10.15252/embr.201846518;
RA Pham C.L., Shanmugam N., Strange M., O'Carroll A., Brown J.W., Sierecki E.,
RA Gambin Y., Steain M., Sunde M.;
RT "Viral M45 and necroptosis-associated proteins form heteromeric amyloid
RT assemblies.";
RL EMBO Rep. 20:0-0(2019).
CC -!- FUNCTION: Provides optimal viral replication conditions by promoting
CC host cell survival and avoiding the host inflammatory response linked
CC to NF-kappa-B activation. Blocks RIPK1 ubiquitination, thereby
CC preventing NF-kappa-B activation and virally induced inflammatory
CC response. Prevents host necroptosis by targeting RIPK3 thereby
CC preventing the formation of necroptotic RIPK1-RIPK3 complexes. Also
CC inhibits ZBP1-induced necroptosis. Does not have ribonucleotide
CC reductase activity. Betaherpesviruses probably use another strategy to
CC expand the dNTP pool in a quiescent host cell.
CC {ECO:0000269|PubMed:11209080, ECO:0000269|PubMed:18287053,
CC ECO:0000269|PubMed:18442983, ECO:0000269|PubMed:19590578,
CC ECO:0000269|PubMed:20413098, ECO:0000269|PubMed:28716805,
CC ECO:0000269|PubMed:30498077}.
CC -!- SUBUNIT: Self-assembles into homo-oligomeric amyloid fibrils. Interacts
CC with host RIPK1 (via RIP homotypic interaction motif); this interaction
CC inhibits RIPK1 ubiquitination thereby preventing effective activation
CC of host NF-kappa-B. Interacts with host RIPK3 (via RIP homotypic
CC interaction motif); this interaction disrupts RIPK3-RIPK1 interactions
CC characteristic of TNF-alpha induced necroptosis, thereby suppressing
CC this death pathway. Interacts (via RIP homotypic interaction motif)
CC with host ZBP1 (via RIP homotypic interaction motif); this interaction
CC inhibits recruitment of RIPK1 and RIPK3 to ZBP1 and prevents ZBP1-
CC induced NF-kappa-B activation. {ECO:0000269|PubMed:18287053,
CC ECO:0000269|PubMed:18442983, ECO:0000269|PubMed:19590578,
CC ECO:0000269|PubMed:20413098, ECO:0000269|PubMed:30498077}.
CC -!- INTERACTION:
CC Q06A28; Q62172: Ralbp1; Xeno; NbExp=2; IntAct=EBI-9826498, EBI-8392197;
CC -!- SUBCELLULAR LOCATION: Virion {ECO:0000255|HAMAP-Rule:MF_04027,
CC ECO:0000269|PubMed:15047841}. Host cytoplasm. Note=Starts to be
CC expressed at 12 h after infection and accumulates in the cytoplasm of
CC the infected cells. {ECO:0000255|HAMAP-Rule:MF_04027,
CC ECO:0000269|PubMed:15047841}.
CC -!- DOMAIN: The N-terminal region drives rapid self-assembly into homo-
CC oligomeric amyloid fibrils and interacts with the RHIMs of host kinases
CC RIPK1 and RIPK3, and ZBP1 to form heteromeric amyloid fibrils.
CC {ECO:0000269|PubMed:30498077}.
CC -!- PTM: Undergoes proteolytic cleavage, generating two peptides, a N-
CC terminal and a 116 kDa. The N-terminal peptide retains RIPK1- and
CC RIPK3-binding activity as well as cell death suppression activity.
CC {ECO:0000269|PubMed:15047841}.
CC -!- SIMILARITY: Belongs to the ribonucleoside diphosphate reductase large
CC chain family. {ECO:0000255|HAMAP-Rule:MF_04027}.
CC -!- CAUTION: Lacks the conserved sequence Asn-x-Cys-x-Glu essential for
CC ribonucleotide reductase activity. {ECO:0000255|HAMAP-Rule:MF_04027}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; U68299; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; DQ978788; ABI94733.1; -; Genomic_DNA.
DR EMBL; GU305914; ADD10427.1; -; Genomic_DNA.
DR SMR; Q06A28; -.
DR DIP; DIP-29743N; -.
DR IntAct; Q06A28; 4.
DR Proteomes; UP000008774; Genome.
DR Proteomes; UP000180711; 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:0006260; P:DNA replication; IEA:InterPro.
DR GO; GO:0039644; P:suppression by virus of host NF-kappaB cascade; IEA:UniProtKB-KW.
DR HAMAP; MF_04027; HSV_RIR1_betahv; 1.
DR InterPro; IPR034716; HSV_RIR1_betahv.
DR InterPro; IPR025735; RHIM_dom.
DR InterPro; IPR000788; RNR_lg_C.
DR InterPro; IPR039718; Rrm1.
DR PANTHER; PTHR11573; PTHR11573; 1.
DR Pfam; PF12721; RHIM; 1.
DR Pfam; PF02867; Ribonuc_red_lgC; 1.
DR PRINTS; PR01183; RIBORDTASEM1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Host cytoplasm; Host-virus interaction;
KW Inhibition of host NF-kappa-B by virus; Late protein; Reference proteome;
KW Virion.
FT CHAIN 1..1174
FT /note="Ribonucleoside-diphosphate reductase large subunit-
FT like protein"
FT /id="PRO_0000412111"
FT CHAIN 1..277
FT /note="N-terminal peptide"
FT /id="PRO_0000412112"
FT CHAIN 278..1174
FT /note="116 kDa peptide"
FT /id="PRO_0000412113"
FT REGION 170..269
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 291..325
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 50..72
FT /note="RIP homotypic interaction motif (RHIM)"
FT /evidence="ECO:0000269|PubMed:20413098,
FT ECO:0000269|PubMed:28716805"
FT COMPBIAS 171..221
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 250..265
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 277..278
FT /note="Cleavage"
FT MUTAGEN 61..64
FT /note="IQIG->AAAA: In M45mut(RHIM); abolished ability to
FT prevent necroptosis in infected cells."
FT /evidence="ECO:0000269|PubMed:20413098,
FT ECO:0000269|PubMed:28716805"
SQ SEQUENCE 1174 AA; 125215 MW; BDDC93B8E71E40C7 CRC64;
MDRQPKVYSD PDNGFFFLDV PMPDDGQGGQ QTATTAAGGA FGVGGGHSVP YVRIMNGVSG
IQIGNHNAMS IASCWSPSYT DRRRRSYPKT ATNAAADRVA AAVSAANAAV NAAAAAAAAG
GGGGANLLAA AVTCANQRGC CGGNGGHSLP PTRMPKTNAT AAAAPAVAGA SNAKSDNNHA
NATSGAGSAA ATPAATTPAA TAVENRRPSP SPSTASTAPC DEGSSPRHHR PSHVSVGTQA
TPSTPIPIPA PRCSTGQQQQ QPQAKKLKPA KADPLLYAAT MPPPASVTTA AAAAVAPESE
SSPAASAPPA AAAMATGGDD EDQSSFSFVS DDVLGEFEDL RIAGLPVRDE MRPPTPTMTV
IPVSRPFRAG RDSGRDALFD DAVESVRCYC HGILGNSRFC ALVNEKCSEP AKERMARIRR
YAADVTRCGP LALYTAIVSS ANRLIQTDPS CDLDLAECYV ETASKRNAVP LSAFYRDCDR
LRDAVAAFFK TYGMVVDAMA QRITERVGPA LGRGLYSTVV MMDRCGNSFQ GREETPISVF
ARVAAALAVE CEVDGGVSYK ILSSKPVDAA QAFDAFLSAL CSFAIIPSPR VLAYAGFGGS
NPIFDAVSYR AQFYSAESTI NGTLHDICDM VTNGLSVSVS AADLGGDIVA SLHILGQQCK
ALRPYARFKT VLRIYFDIWS VDALKIFSFI LDVGREYEGL MAFAVNTPRI FWDRYLDSSG
DKMWLMFARR EAAALCGLDL KSFRNVYEKM ERDGRSAITV SPWWAVCQLD ACVARGNTAV
VFPHNVKSMI PENIGRPAVC GPGVSVVSGG FVGCTPIHEL CINLENCVLE GAAVESSVDV
VLGLGCRFSF KALESLVRDA VVLGNLLIDM TVRTNAYGAG KLLTLYRDLH IGVVGFHAVM
NRLGQKFADM ESYDLNQRIA EFIYYTAVRA SVDLCMAGAD PFPKFPKSLY AAGRFYPDLF
DDDERGPRRM TKEFLEKLRE DVVKHGIRNA SFITGCSADE AANLAGTTPG FWPRRDNVFL
EQTPLMMTPT KDQMLDECVR SVKIEPHRLH EEDLSCLGEN RPVELPVLNS RLRQISKESA
TVAVRRGRSA PFYDDSDDED EVACSETGWT VSTDAVIKMC VDRQPFVDHA QSLPVAIGFG
GSSVELARHL RRGNALGLSV GVYKCSMPPS VNYR
