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Protein

Nucleotide-binding oligomerization domain-containing protein 2

Gene

Nod2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Recognizes muramyl dipeptide (MDP) constituents of bacterial peptidoglycans and plays a key role in gastrointestinal immunity: upon stimulation, binds the proximal adapter receptor-interacting RIPK2, which recruits ubiquitin ligases as XIAP, BIRC2, BIRC3 and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling, leading to activate the transcription of hundreds of genes involved in immune response.1 Publication

GO - Molecular functioni

GO - Biological processi

  • activation of immune response Source: MGI
  • activation of MAPK activity involved in innate immune response Source: BHF-UCL
  • cellular response to muramyl dipeptide Source: UniProtKB
  • cellular response to peptidoglycan Source: MGI
  • cytokine production involved in immune response Source: UniProtKB
  • cytokine secretion involved in immune response Source: MGI
  • defense response Source: HGNC
  • defense response to bacterium Source: HGNC
  • defense response to Gram-positive bacterium Source: MGI
  • detection of bacterium Source: HGNC
  • detection of biotic stimulus Source: HGNC
  • detection of muramyl dipeptide Source: HGNC
  • immunoglobulin production involved in immunoglobulin mediated immune response Source: MGI
  • inflammatory response Source: HGNC
  • innate immune response Source: UniProtKB
  • innate immune response in mucosa Source: MGI
  • intracellular signal transduction Source: UniProtKB
  • macrophage inflammatory protein-1 alpha production Source: MGI
  • maintenance of gastrointestinal epithelium Source: MGI
  • negative regulation of growth of symbiont in host Source: MGI
  • negative regulation of inflammatory response to antigenic stimulus Source: MGI
  • negative regulation of interferon-gamma production Source: MGI
  • negative regulation of interleukin-12 production Source: MGI
  • negative regulation of interleukin-18 production Source: MGI
  • negative regulation of interleukin-2 production Source: MGI
  • negative regulation of macrophage apoptotic process Source: BHF-UCL
  • negative regulation of NF-kappaB transcription factor activity Source: MGI
  • negative regulation of T cell mediated immunity Source: MGI
  • negative regulation of toll-like receptor 2 signaling pathway Source: MGI
  • negative regulation of tumor necrosis factor production Source: MGI
  • nucleotide-binding oligomerization domain containing 2 signaling pathway Source: UniProtKB
  • positive regulation of antibacterial peptide biosynthetic process Source: MGI
  • positive regulation of B cell activation Source: MGI
  • positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria Source: MGI
  • positive regulation of cytokine production involved in inflammatory response Source: MGI
  • positive regulation of dendritic cell antigen processing and presentation Source: BHF-UCL
  • positive regulation of epithelial cell proliferation Source: BHF-UCL
  • positive regulation of ERK1 and ERK2 cascade Source: BHF-UCL
  • positive regulation of humoral immune response mediated by circulating immunoglobulin Source: MGI
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: HGNC
  • positive regulation of innate immune response Source: MGI
  • positive regulation of interleukin-10 production Source: BHF-UCL
  • positive regulation of interleukin-12 production Source: MGI
  • positive regulation of interleukin-17 production Source: UniProtKB
  • positive regulation of interleukin-1 beta production Source: MGI
  • positive regulation of interleukin-1 beta secretion Source: UniProtKB
  • positive regulation of interleukin-6 production Source: MGI
  • positive regulation of JNK cascade Source: MGI
  • positive regulation of MAPK cascade Source: MGI
  • positive regulation of monocyte chemotactic protein-1 production Source: UniProtKB
  • positive regulation of NF-kappaB transcription factor activity Source: HGNC
  • positive regulation of nitric-oxide synthase biosynthetic process Source: BHF-UCL
  • positive regulation of Notch signaling pathway Source: BHF-UCL
  • positive regulation of oxidoreductase activity Source: BHF-UCL
  • positive regulation of peptidyl-tyrosine phosphorylation Source: MGI
  • positive regulation of phagocytosis Source: MGI
  • positive regulation of phosphatidylinositol 3-kinase activity Source: BHF-UCL
  • positive regulation of prostaglandin-endoperoxide synthase activity Source: BHF-UCL
  • positive regulation of prostaglandin-E synthase activity Source: BHF-UCL
  • positive regulation of protein ubiquitination Source: UniProtKB
  • positive regulation of stress-activated MAPK cascade Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of tumor necrosis factor production Source: MGI
  • positive regulation of type 2 immune response Source: BHF-UCL
  • protein oligomerization Source: HGNC
  • regulation of inflammatory response Source: MGI
  • regulation of neutrophil chemotaxis Source: MGI
  • response to exogenous dsRNA Source: MGI
  • response to lipopolysaccharide Source: MGI
  • response to muramyl dipeptide Source: HGNC
  • response to peptidoglycan Source: MGI
  • signal transduction Source: HGNC
Complete GO annotation...

Keywords - Biological processi

Immunity, Innate immunity

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiREACT_288310. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
REACT_301153. NOD1/2 Signaling Pathway.
REACT_305279. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_324009. activated TAK1 mediates p38 MAPK activation.
REACT_337033. Interleukin-1 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Nucleotide-binding oligomerization domain-containing protein 2
Alternative name(s):
Caspase recruitment domain-containing protein 15
Gene namesi
Name:Nod2
Synonyms:Card15
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 8

Organism-specific databases

MGIiMGI:2429397. Nod2.

Subcellular locationi

  • Cytoplasm By similarity
  • Membrane By similarity
  • Basolateral cell membrane By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 10201020Nucleotide-binding oligomerization domain-containing protein 2PRO_0000144091Add
BLAST

Post-translational modificationi

Polyubiquitinated following MDP stimulation, leading to proteasome-mediated degradation.By similarity

Keywords - PTMi

Ubl conjugation

Proteomic databases

PRIDEiQ8K3Z0.

PTM databases

PhosphoSiteiQ8K3Z0.

Expressioni

Gene expression databases

BgeeiQ8K3Z0.
ExpressionAtlasiQ8K3Z0. baseline and differential.

Interactioni

Subunit structurei

Found in a signaling complex consisting of ARHGEF2, NOD2 and RIPK2 (By similarity). Interacts (via CARD domain) with RIPK2 (via CARD domain) (By similarity). Interacts with ATG16L1 (By similarity). Interacts (via NACHT domain) with CARD9 (PubMed:17187069). Interacts with ANKRD17 (via N-terminus) (By similarity). Interacts with HSPA1A; the interaction enhances NOD2 stability (By similarity). Interacts (via both CARD domains) with HSP90; the interaction enhances NOD2 stability (PubMed:23019338). Interacts (via CARD domain) with SOCS3; the interaction promotes NOD2 degradation (PubMed:23019338). Interacts (via CARD domain) with ERBB2IP; the interaction inhibits activation of NOD2 (PubMed:16203728).By similarity3 Publications

Protein-protein interaction databases

DIPiDIP-46115N.
IntActiQ8K3Z0. 1 interaction.
STRINGi10090.ENSMUSP00000113773.

Structurei

3D structure databases

ProteinModelPortaliQ8K3Z0.
SMRiQ8K3Z0. Positions 760-1012.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini6 – 10499CARD 1PROSITE-ProRule annotationAdd
BLAST
Domaini106 – 20095CARD 2PROSITE-ProRule annotationAdd
BLAST
Domaini273 – 600328NACHTPROSITE-ProRule annotationAdd
BLAST
Repeati685 – 70925LRR 1Add
BLAST
Repeati726 – 74924LRR 2Add
BLAST
Repeati766 – 79227LRR 3Add
BLAST
Repeati794 – 81724LRR 4Add
BLAST
Repeati822 – 84524LRR 5Add
BLAST
Repeati850 – 87324LRR 6Add
BLAST
Repeati906 – 92924LRR 7Add
BLAST
Repeati934 – 96229LRR 8Add
BLAST
Repeati963 – 98523LRR 9Add
BLAST
Repeati1005 – 101915LRR 10Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni221 – 25434Required for CARD9 bindingBy similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi43 – 5715ATG16L1-binding motifAdd
BLAST

Domaini

The ATG16L1-binding motif mediates interaction with ATG16L1.By similarity

Sequence similaritiesi

Contains 2 CARD domains.PROSITE-ProRule annotation
Contains 10 LRR (leucine-rich) repeats.Curated
Contains 1 NACHT domain.PROSITE-ProRule annotation

Keywords - Domaini

Leucine-rich repeat, Repeat

Phylogenomic databases

eggNOGiNOG248107.
GeneTreeiENSGT00800000124023.
HOGENOMiHOG000113814.
HOVERGENiHBG050792.
InParanoidiQ8K3Z0.
OMAiFDEFKFR.
PhylomeDBiQ8K3Z0.
TreeFamiTF352118.

Family and domain databases

Gene3Di1.10.533.10. 2 hits.
InterProiIPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR018228. DNase_TatD-rel_CS.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF00619. CARD. 2 hits.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 2 hits.
SSF52540. SSF52540. 1 hit.
PROSITEiPS50209. CARD. 2 hits.
PS50837. NACHT. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8K3Z0-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MRSSCCDMCS QEEFQAQRSQ LVALLISGSL EGFESILDWL LSWDVLSRED
60 70 80 90 100
YEGLSLPGQP LSHSARRLLD TVWNKGVWGC QKLLEAVQEA QANSHTFELY
110 120 130 140 150
GSWDTHSLHP TRDLQSHRPA IVRRLYNHVE AMLELAREGG FLSQYECEEI
160 170 180 190 200
RLPIFTSSQR ARRLLDLAAV KANGLAAFLL QHVRELPAPL PLPYEAAECQ
210 220 230 240 250
KFISKLRTMV LTQSRFLSTY DGSENLCLED IYTENILELQ TEVGTAGALQ
260 270 280 290 300
KSPAILGLED LFDTHGHLNR DADTILVVGE AGSGKSTLLQ RLHLLWATGR
310 320 330 340 350
SFQEFLFIFP FSCRQLQCVA KPLSLRTLLF EHCCWPDVAQ DDVFQFLLDH
360 370 380 390 400
PDRVLLTFDG LDEFKFRFTD RERHCSPIDP TSVQTLLFNL LQGNLLKNAC
410 420 430 440 450
KVLTSRPDAV SALLRKFVRT ELQLKGFSEE GIQLYLRKHH REPGVADRLI
460 470 480 490 500
QLIQATSALH GLCHLPVFSW MVSRCHRELL LQNRGFPTTS TDMYLLILQH
510 520 530 540 550
FLLHASPPDS SPLGLGPGLL QSRLSTLLHL GHLALRGLAM SCYVFSAQQL
560 570 580 590 600
QAAQVDSDDI SLGFLVRAQS SVPGSKAPLE FLHITFQCFF AAFYLAVSAD
610 620 630 640 650
TSVASLKHLF SCGRLGSSLL GRLLPNLCIQ GSRVKKGSEA ALLQKAEPHN
660 670 680 690 700
LQITAAFLAG LLSQQHRDLL AACQVSERVL LQRQARARSC LAHSLREHFH
710 720 730 740 750
SIPPAVPGET KSMHAMPGFI WLIRSLYEMQ EEQLAQEAVR RLDIGHLKLT
760 770 780 790 800
FCRVGPAECA ALAFVLQHLQ RPVALQLDYN SVGDVGVEQL RPCLGVCTAL
810 820 830 840 850
YLRDNNISDR GARTLVECAL RCEQLQKLAL FNNKLTDACA CSMAKLLAHK
860 870 880 890 900
QNFLSLRVGN NHITAAGAEV LAQGLKSNTS LKFLGFWGNS VGDKGTQALA
910 920 930 940 950
EVVADHQNLK WLSLVGNNIG SMGAEALALM LEKNKSLEEL CLEENHICDE
960 970 980 990 1000
GVYSLAEGLK RNSTLKFLKL SNNGITYRGA EALLQALSRN SAILEVWLRG
1010 1020
NTFSLEEIQT LSSRDARLLL
Length:1,020
Mass (Da):113,562
Last modified:October 1, 2002 - v1
Checksum:i25504905ECF70FBB
GO
Isoform 2 (identifier: Q8K3Z0-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-7: Missing.
     195-195: E → EGYSLCRSRCDRGFTLICLFCIL

Note: No experimental confirmation available.
Show »
Length:1,035
Mass (Da):115,301
Checksum:i7F0E533DC98068FD
GO

Sequence cautioni

The sequence AAH44774.1 differs from that shown. Reason: Erroneous initiation. Curated

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti212 – 2121T → A in strain: NMRI. 1 Publication
Natural varianti240 – 2401Q → R in strain: NMRI. 1 Publication
Natural varianti422 – 4221L → C in strain: NMRI; requires 2 nucleotide substitutions. 1 Publication
Natural varianti485 – 4851G → V in strain: NMRI. 1 Publication
Natural varianti603 – 6031V → A in strain: NMRI. 1 Publication
Natural varianti675 – 6751V → I in strain: NMRI. 1 Publication
Natural varianti925 – 9251E → Q in strain: NMRI. 1 Publication

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei1 – 77Missing in isoform 2. 1 PublicationVSP_007069
Alternative sequencei195 – 1951E → EGYSLCRSRCDRGFTLICLF CIL in isoform 2. 1 PublicationVSP_007070

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF520774 mRNA. Translation: AAM76073.1.
BC044774 mRNA. Translation: AAH44774.1. Different initiation.
UniGeneiMm.222633.

Genome annotation databases

EnsembliENSMUST00000054324; ENSMUSP00000050538; ENSMUSG00000055994. [Q8K3Z0-2]
ENSMUST00000109634; ENSMUSP00000105262; ENSMUSG00000055994. [Q8K3Z0-1]
UCSCiuc009mrq.1. mouse. [Q8K3Z0-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF520774 mRNA. Translation: AAM76073.1.
BC044774 mRNA. Translation: AAH44774.1. Different initiation.
UniGeneiMm.222633.

3D structure databases

ProteinModelPortaliQ8K3Z0.
SMRiQ8K3Z0. Positions 760-1012.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-46115N.
IntActiQ8K3Z0. 1 interaction.
STRINGi10090.ENSMUSP00000113773.

PTM databases

PhosphoSiteiQ8K3Z0.

Proteomic databases

PRIDEiQ8K3Z0.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000054324; ENSMUSP00000050538; ENSMUSG00000055994. [Q8K3Z0-2]
ENSMUST00000109634; ENSMUSP00000105262; ENSMUSG00000055994. [Q8K3Z0-1]
UCSCiuc009mrq.1. mouse. [Q8K3Z0-1]

Organism-specific databases

MGIiMGI:2429397. Nod2.

Phylogenomic databases

eggNOGiNOG248107.
GeneTreeiENSGT00800000124023.
HOGENOMiHOG000113814.
HOVERGENiHBG050792.
InParanoidiQ8K3Z0.
OMAiFDEFKFR.
PhylomeDBiQ8K3Z0.
TreeFamiTF352118.

Enzyme and pathway databases

ReactomeiREACT_288310. JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
REACT_301153. NOD1/2 Signaling Pathway.
REACT_305279. TAK1 activates NFkB by phosphorylation and activation of IKKs complex.
REACT_324009. activated TAK1 mediates p38 MAPK activation.
REACT_337033. Interleukin-1 signaling.

Miscellaneous databases

PROiQ8K3Z0.
SOURCEiSearch...

Gene expression databases

BgeeiQ8K3Z0.
ExpressionAtlasiQ8K3Z0. baseline and differential.

Family and domain databases

Gene3Di1.10.533.10. 2 hits.
InterProiIPR001315. CARD.
IPR011029. DEATH-like_dom.
IPR018228. DNase_TatD-rel_CS.
IPR007111. NACHT_NTPase.
IPR027417. P-loop_NTPase.
[Graphical view]
PfamiPF00619. CARD. 2 hits.
[Graphical view]
SUPFAMiSSF47986. SSF47986. 2 hits.
SSF52540. SSF52540. 1 hit.
PROSITEiPS50209. CARD. 2 hits.
PS50837. NACHT. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Cloning, sequencing and expression analysis of the mouse Nod2/Card15 gene."
    Iwanaga Y., Davey M.P., Martin T.M., Planck S.R., DePriest M.L., Baugh M.M., Suing C.M., Rosenbaum J.T.
    Inflamm. Res. 52:272-276(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Strain: BALB/c.
    Tissue: Monocyte.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), VARIANTS ALA-212; ARG-240; CYS-422; VAL-485; ALA-603; ILE-675 AND GLN-925.
    Strain: NMRI.
    Tissue: Mammary cancer.
  3. "A role for Erbin in the regulation of Nod2-dependent NF-kappaB signaling."
    McDonald C., Chen F.F., Ollendorff V., Ogura Y., Marchetto S., Lecine P., Borg J.P., Nunez G.
    J. Biol. Chem. 280:40301-40309(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ERBB2IP.
  4. "The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens."
    Hsu Y.M., Zhang Y., You Y., Wang D., Li H., Duramad O., Qin X.F., Dong C., Lin X.
    Nat. Immunol. 8:198-205(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CARD9.
  5. "Proteasomal degradation of Nod2 protein mediates tolerance to bacterial cell wall components."
    Lee K.H., Biswas A., Liu Y.J., Kobayashi K.S.
    J. Biol. Chem. 287:39800-39811(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH HSP90 AND SOCS3.
  6. Cited for: FUNCTION.

Entry informationi

Entry nameiNOD2_MOUSE
AccessioniPrimary (citable) accession number: Q8K3Z0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: March 28, 2003
Last sequence update: October 1, 2002
Last modified: July 22, 2015
This is version 123 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.