ID   NOD2_BOVIN              Reviewed;        1013 AA.
AC   Q6E804;
DT   26-MAY-2009, integrated into UniProtKB/Swiss-Prot.
DT   16-AUG-2004, sequence version 1.
DT   07-SEP-2016, entry version 102.
DE   RecName: Full=Nucleotide-binding oligomerization domain-containing protein 2;
DE            EC=2.3.1.234 {ECO:0000255|HAMAP-Rule:MF_01445, ECO:0000269|PubMed:22378793};
DE   AltName: Full=Caspase recruitment domain-containing protein 15;
DE            EC=6.3.1.999;
GN   Name=NOD2 {ECO:0000255|HAMAP-Rule:MF_01445}; Synonyms=CARD15;
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Laurasiatheria; Cetartiodactyla; Ruminantia;
OC   Pecora; Bovidae; Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANTS ALA-70;
RP   MET-196; ASN-505; GLN-681; HIS-689; ARG-733 AND LEU-1007.
RX   PubMed=16897345; DOI=10.1007/s00335-005-0148-2;
RA   Taylor K.H., Taylor J.F., White S.N., Womack J.E.;
RT   "Identification of genetic variation and putative regulatory regions
RT   in bovine CARD15.";
RL   Mamm. Genome 17:892-901(2006).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RX   PubMed=20698950; DOI=10.1186/1756-0500-3-224;
RA   Kramer M., Boeck J., Reichenbach D., Kaether C., Schreiber S.,
RA   Platzer M., Rosenstiel P., Huse K.;
RT   "NOD2-C2 - a novel NOD2 isoform activating NF-kappaB in a muramyl
RT   dipeptide-independent manner.";
RL   BMC Res. Notes 3:224-224(2010).
RN   [3]
RP   INTERACTION WITH ERBBI2P, AND SUBCELLULAR LOCATION.
RX   PubMed=16203728; DOI=10.1074/jbc.M508538200;
RA   McDonald C., Chen F.F., Ollendorff V., Ogura Y., Marchetto S.,
RA   Lecine P., Borg J.P., Nunez G.;
RT   "A role for Erbin in the regulation of Nod2-dependent NF-kappaB
RT   signaling.";
RL   J. Biol. Chem. 280:40301-40309(2005).
RN   [4]
RP   FUNCTION, INTERACTION WITH CASP1; CASP4 AND NLRP1, AUTOINHIBITION, AND
RP   DOMAIN.
RX   PubMed=18511561; DOI=10.1073/pnas.0802726105;
RA   Hsu L.C., Ali S.R., McGillivray S., Tseng P.H., Mariathasan S.,
RA   Humke E.W., Eckmann L., Powell J.J., Nizet V., Dixit V.M., Karin M.;
RT   "A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion
RT   in response to Bacillus anthracis infection and muramyl dipeptide.";
RL   Proc. Natl. Acad. Sci. U.S.A. 105:7803-7808(2008).
RN   [5]
RP   INTERACTION WITH RIPK2.
RX   PubMed=19592251; DOI=10.1016/j.cub.2009.06.038;
RA   Tao M., Scacheri P.C., Marinis J.M., Harhaj E.W., Matesic L.E.,
RA   Abbott D.W.;
RT   "ITCH K63-ubiquitinates the NOD2 binding protein, RIP2, to influence
RT   inflammatory signaling pathways.";
RL   Curr. Biol. 19:1255-1263(2009).
RN   [6]
RP   IDENTIFICATION IN A COMPLEX WITH ARHGEF2 AND RIPK2, AND INTERACTION
RP   WITH RIPK2.
RX   PubMed=21887730; DOI=10.1002/ibd.21851;
RA   Zhao Y., Alonso C., Ballester I., Song J.H., Chang S.Y., Guleng B.,
RA   Arihiro S., Murray P.J., Xavier R., Kobayashi K.S., Reinecker H.C.;
RT   "Control of NOD2 and Rip2-dependent innate immune activation by GEF-
RT   H1.";
RL   Inflamm. Bowel Dis. 18:603-612(2012).
CC   -!- FUNCTION: Involved in gastrointestinal immunity. Upon stimulation
CC       by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan,
CC       binds the proximal adapter receptor-interacting RIPK2, which
CC       recruits ubiquitin ligases as XIAP, BIRC2, BIRC3 and the LUBAC
CC       complex, triggering activation of MAP kinases and activation of
CC       NF-kappa-B signaling. This in turn leads to the transcriptional
CC       activation of hundreds of genes involved in immune response.
CC       Required for MDP-induced NLRP1-dependent CASP1 activation and IL1B
CC       release in macrophages. {ECO:0000250|UniProtKB:Q9HC29}.
CC   -!- SUBUNIT: Component of a signaling complex consisting of ARHGEF2,
CC       NOD2 and RIPK2. Interacts (via CARD domain) with RIPK2 (via CARD
CC       domain). Interacts with ATG16L1. Interacts (via NACHT domain) with
CC       CARD9. Interacts with ANKRD17 (via N-terminus). Interacts with
CC       HSPA1A; the interaction enhances NOD2 stability. Interacts (via
CC       both CARD domains) with HSP90; the interaction enhances NOD2
CC       stability. Interacts (via CARD domain) with SOCS3; the interaction
CC       promotes NOD2 degradation. Interacts (via CARD domain) with
CC       ERBBI2P; the interaction inhibits activation of NOD2. Interacts
CC       (via CARD domain) with CASP1; this interaction leads to IL1B
CC       processing. Also interacts with CASP4. Interacts with NLRP1; this
CC       interaction is enhanced in the presence of muramyl dipeptide (MDP)
CC       and leads to increased IL1B release.
CC       {ECO:0000250|UniProtKB:Q9HC29}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9HC29}.
CC       Membrane {ECO:0000250|UniProtKB:Q9HC29}. Basolateral cell membrane
CC       {ECO:0000250|UniProtKB:Q9HC29}.
CC   -!- DOMAIN: The ATG16L1-binding motif mediates interaction with
CC       ATG16L1. {ECO:0000250}.
CC   -!- DOMAIN: Intramolecular interactions between the N-terminal moiety
CC       and the leucine-rich repeats (LRR) may be important for
CC       autoinhibition in the absence of activating signal. In the absence
CC       of LRRs, the protein becomes a constitutive activator of CASP1
CC       cleavage and proIL1B processing. {ECO:0000250|UniProtKB:Q9HC29}.
CC   -!- PTM: Polyubiquitinated following MDP stimulation, leading to
CC       proteasome-mediated degradation. {ECO:0000250|UniProtKB:Q9HC29}.
CC   -!- SIMILARITY: Contains 2 CARD domains. {ECO:0000255|PROSITE-
CC       ProRule:PRU00046}.
CC   -!- SIMILARITY: Contains 9 LRR (leucine-rich) repeats. {ECO:0000305}.
CC   -!- SIMILARITY: Contains 1 NACHT domain. {ECO:0000255|PROSITE-
CC       ProRule:PRU00136}.
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DR   EMBL; AY518737; AAS09824.1; -; mRNA.
DR   EMBL; AY518748; AAS09826.1; -; Genomic_DNA.
DR   EMBL; AY518739; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518740; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518741; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518742; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518743; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518744; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518745; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518746; AAS09826.1; JOINED; Genomic_DNA.
DR   EMBL; AY518747; AAS09826.1; JOINED; Genomic_DNA.
DR   RefSeq; NP_001002889.1; NM_001002889.1.
DR   RefSeq; XP_005218524.1; XM_005218467.3.
DR   RefSeq; XP_010812724.1; XM_010814422.2.
DR   RefSeq; XP_015331193.1; XM_015475707.1.
DR   UniGene; Bt.30778; -.
DR   ProteinModelPortal; Q6E804; -.
DR   STRING; 9913.ENSBTAP00000027887; -.
DR   PaxDb; Q6E804; -.
DR   Ensembl; ENSBTAT00000027887; ENSBTAP00000027887; ENSBTAG00000020936.
DR   GeneID; 444867; -.
DR   KEGG; bta:444867; -.
DR   CTD; 64127; -.
DR   eggNOG; KOG4308; Eukaryota.
DR   eggNOG; ENOG410ZBX3; LUCA.
DR   GeneTree; ENSGT00840000129782; -.
DR   HOGENOM; HOG000113814; -.
DR   InParanoid; Q6E804; -.
DR   KO; K10165; -.
DR   OMA; FDEFKFR; -.
DR   OrthoDB; EOG091G01CG; -.
DR   TreeFam; TF352118; -.
DR   Reactome; R-BTA-168638; NOD1/2 Signaling Pathway.
DR   Reactome; R-BTA-445989; TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
DR   Reactome; R-BTA-446652; Interleukin-1 signaling.
DR   Reactome; R-BTA-450302; activated TAK1 mediates p38 MAPK activation.
DR   Reactome; R-BTA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR   Proteomes; UP000009136; Chromosome 18.
DR   Bgee; ENSBTAG00000020936; -.
DR   GO; GO:0016323; C:basolateral plasma membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR   GO; GO:0008180; C:COP9 signalosome; IEA:Ensembl.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005856; C:cytoskeleton; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR   GO; GO:0043234; C:protein complex; ISS:UniProtKB.
DR   GO; GO:0031982; C:vesicle; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0032500; F:muramyl dipeptide binding; IEA:Ensembl.
DR   GO; GO:0042834; F:peptidoglycan binding; IEA:Ensembl.
DR   GO; GO:0071225; P:cellular response to muramyl dipeptide; ISS:UniProtKB.
DR   GO; GO:0002374; P:cytokine secretion involved in immune response; IEA:Ensembl.
DR   GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR   GO; GO:0016045; P:detection of bacterium; IEA:Ensembl.
DR   GO; GO:0032498; P:detection of muramyl dipeptide; IEA:Ensembl.
DR   GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR   GO; GO:0030277; P:maintenance of gastrointestinal epithelium; IEA:Ensembl.
DR   GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; ISS:UniProtKB.
DR   GO; GO:0050871; P:positive regulation of B cell activation; IEA:Ensembl.
DR   GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IEA:Ensembl.
DR   GO; GO:0046645; P:positive regulation of gamma-delta T cell activation; IMP:BHF-UCL.
DR   GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR   GO; GO:0050718; P:positive regulation of interleukin-1 beta secretion; IEA:Ensembl.
DR   GO; GO:0032740; P:positive regulation of interleukin-17 production; IEA:Ensembl.
DR   GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR   GO; GO:0032757; P:positive regulation of interleukin-8 production; IEA:Ensembl.
DR   GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR   GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR   GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR   GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:UniProtKB.
DR   GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR   GO; GO:0002830; P:positive regulation of type 2 immune response; ISS:BHF-UCL.
DR   GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR   GO; GO:0032495; P:response to muramyl dipeptide; IDA:BHF-UCL.
DR   Gene3D; 1.10.533.10; -; 2.
DR   Gene3D; 3.80.10.10; -; 1.
DR   InterPro; IPR001315; CARD.
DR   InterPro; IPR011029; DEATH-like_dom.
DR   InterPro; IPR032675; L_dom-like.
DR   InterPro; IPR001611; Leu-rich_rpt.
DR   InterPro; IPR007111; NACHT_NTPase.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   Pfam; PF00619; CARD; 2.
DR   Pfam; PF13516; LRR_6; 4.
DR   SUPFAM; SSF47986; SSF47986; 2.
DR   SUPFAM; SSF52540; SSF52540; 1.
DR   PROSITE; PS50209; CARD; 2.
DR   PROSITE; PS51450; LRR; 5.
DR   PROSITE; PS50837; NACHT; 1.
PE   2: Evidence at transcript level;
KW   ATP-binding; Cell membrane; Complete proteome; Cytoplasm; Immunity;
KW   Innate immunity; Leucine-rich repeat; Membrane; Nucleotide-binding;
KW   Polymorphism; Reference proteome; Repeat; Ubl conjugation.
FT   CHAIN         1   1013       Nucleotide-binding oligomerization
FT                                domain-containing protein 2.
FT                                /FTId=PRO_0000375804.
FT   DOMAIN        1     95       CARD 1. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00046}.
FT   DOMAIN       99    191       CARD 2. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00046}.
FT   DOMAIN      266    591       NACHT. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00136}.
FT   REPEAT      764    785       LRR 1.
FT   REPEAT      789    809       LRR 2.
FT   REPEAT      817    838       LRR 3.
FT   REPEAT      845    866       LRR 4.
FT   REPEAT      873    893       LRR 5.
FT   REPEAT      901    922       LRR 6.
FT   REPEAT      929    949       LRR 7.
FT   REPEAT      957    978       LRR 8.
FT   REPEAT      985   1008       LRR 9.
FT   NP_BIND     272    279       ATP. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00136}.
FT   REGION      214    247       Required for CARD9 binding.
FT                                {ECO:0000250|UniProtKB:Q9HC29}.
FT   MOTIF        36     50       ATG16L1-binding motif.
FT   VARIANT      70     70       T -> A. {ECO:0000269|PubMed:16897345}.
FT   VARIANT     196    196       V -> M. {ECO:0000269|PubMed:16897345}.
FT   VARIANT     505    505       T -> N. {ECO:0000269|PubMed:16897345}.
FT   VARIANT     681    681       R -> Q. {ECO:0000269|PubMed:16897345}.
FT   VARIANT     689    689       R -> H. {ECO:0000269|PubMed:16897345}.
FT   VARIANT     733    733       C -> R. {ECO:0000269|PubMed:16897345}.
FT   VARIANT    1007   1007       Q -> L. {ECO:0000269|PubMed:16897345}.
SQ   SEQUENCE   1013 AA;  112800 MW;  ACAE5F8C4BEFE11B CRC64;
     MCAQDAFQTQ RSQLVELLVS GSLEGFESIL DRLLSREVLS WEDYEGLSLV GQPISHLARR
     LLDTIWNKGT WGCEQLTAAV REAQADSQPP ELPSSWDPHS PHPARDLQSH RPAIVRRLYG
     HVEGVLDLTQ QRGFISQYET DEIRRPIFTS SQRARRLLDL ATVKANGLAA FLLQCIQELP
     VPLALPFEDA ACKKYVSKLR TVISAQSRFL STYDGAENLC LEEVYTENVL EIQMEVGMAG
     PSQQSPTTLG LEELFSTRDH FNKEADTVLV VGEAGSGKST LLQQLHLLWA SGRAFQEFLF
     VFPFSCRQLQ CLVKPLSMRT LLFEHCCWPD LGPQDVFQVL LDHPERILLT FDGFDEFRFR
     FTDQERHCCP TAPTSVQSLL FNLLQGNLLK NARKVLTSRP SAVSASLRKH VRTELSLKGF
     SEEGIELYLR KRHREPGVAD RLLCLLRATS ALHGLCHLPV FSWMVSKCHE ELLLQGRGSP
     KTTTDMYLLI LRHFLLHASP LPLATHGLGP SLIQGRLPTL LHLGRLALWG LGTCCYVFSA
     KQLQAAHVDS EDLSLGFLVL AKRVVPGSTA PLEFLHITFQ CFFAAFYLAL SADTPPSSLR
     HLFQDHRPES SPLARVLPKL FLRGSRCREG SVAALLQGAE PHNLQITGAF LAGLLSQEHR
     SLLAECQASE TALLRRWDCV RRCLTRSLRE HFRSIPPALP GEAKSMHALP GFLWLIRSLY
     EMQEERLARE AVCRLNVGHL KLTFCGVGPA ECAALAFVLR HLRRPVALQL DHNSVGDIGV
     EQLLPCLGVC KALYLRDNNI SDRGICKLVE HALRCEQLQK LALFNNKLTD GCAHSMARLL
     ACKQNFLALR LGNNHITAAG AEVLAQGLRT NNSLQFLGFW GNQVGDEGAQ ALAAALGDHQ
     SLRWLSLVGN NIGSVGAQAL ALMLEKNMAL EELCLEENHV QDEGVCFLAK GLARNSSLKV
     LKLSNNHISS LGAEALLRAL EKNDTILEVW LRGNTFSPEE IEKLSHQDTR LLL
//
