ID NOD2_HUMAN Reviewed; 1040 AA. AC Q9HC29; E2JEQ6; Q96RH5; Q96RH6; Q96RH8; DT 31-JAN-2002, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2001, sequence version 1. DT 27-MAR-2024, entry version 220. DE RecName: Full=Nucleotide-binding oligomerization domain-containing protein 2 {ECO:0000303|PubMed:11087742}; DE AltName: Full=Caspase recruitment domain-containing protein 15 {ECO:0000303|PubMed:11528384}; DE AltName: Full=Inflammatory bowel disease protein 1; GN Name=NOD2 {ECO:0000303|PubMed:11087742, ECO:0000312|HGNC:HGNC:5331}; GN Synonyms=CARD15 {ECO:0000303|PubMed:11528384}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), MUTAGENESIS OF LYS-305, RP VARIANT ARG-908, FUNCTION, SUBUNIT, INTERACTION WITH RIPK2, AND TISSUE RP SPECIFICITY. RC TISSUE=Mammary gland; RX PubMed=11087742; DOI=10.1074/jbc.m008072200; RA Ogura Y., Inohara N., Benito A., Chen F.F., Yamaoka S., Nunez G.; RT "Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and RT activates NF-kappaB."; RL J. Biol. Chem. 276:4812-4818(2001). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1 AND 2), INVOLVEMENT IN IBD1, RP VARIANTS IBD1 THR-140; ARG-157; CYS-235; ARG-248; ASN-291; SER-294; RP VAL-301; TRP-311; VAL-348; ARG-352; CYS-373; SER-414; LEU-431; VAL-432; RP LYS-441; THR-612; VAL-612; TRP-684; TRP-702; CYS-703; CYS-713; GLY-725; RP VAL-755; VAL-758; LYS-778; MET-793; LYS-843; SER-853; VAL-863; THR-885; RP ARG-908 AND ASP-924, AND VARIANTS MET-189; SER-268; SER-289; ASP-918 AND RP ILE-955. RC TISSUE=Leukocyte; RX PubMed=11385576; DOI=10.1038/35079107; RA Hugot J.-P., Chamaillard M., Zouali H., Lesage S., Cezard J.-P., RA Belaiche J., Almer S., Tysk C., O'Morain C.A., Gassull M., Binder V., RA Finkel Y., Cortot A., Modigliani R., Laurent-Puig P., Gower-Rousseau C., RA Macry J., Colombel J.-F., Sahbatou M., Thomas G.; RT "Association of NOD2 leucine-rich repeat variants with susceptibility to RT Crohn's disease."; RL Nature 411:599-603(2001). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND FUNCTION (ISOFORM 3). RX PubMed=20698950; DOI=10.1186/1756-0500-3-224; RA Kramer M., Boeck J., Reichenbach D., Kaether C., Schreiber S., Platzer M., RA 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 [4] RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=14570728; DOI=10.1136/gut.52.11.1591; RA Ogura Y., Lala S., Xin W., Smith E., Dowds T.A., Chen F.F., Zimmermann E., RA Tretiakova M., Cho J.H., Hart J., Greenson J.K., Keshav S., Nunez G.; RT "Expression of NOD2 in Paneth cells: a possible link to Crohn's ileitis."; RL Gut 52:1591-1597(2003). RN [5] RP FUNCTION, VARIANTS IBD1 TRP-702; ARG-908 AND 1007-LEU--LEU-1040 DELINS PRO, RP AND CHARACTERIZATION OF VARIANTS IBD1 TRP-702; ARG-908 AND RP 1007-LEU--LEU-1040 DELINS PRO. RX PubMed=12514169; DOI=10.1074/jbc.c200673200; RA Inohara N., Ogura Y., Fontalba A., Gutierrez O., Pons F., Crespo J., RA Fukase K., Inamura S., Kusumoto S., Hashimoto M., Foster S.J., Moran A.P., RA Fernandez-Luna J.L., Nunez G.; RT "Host recognition of bacterial muramyl dipeptide mediated through NOD2. RT Implications for Crohn's disease."; RL J. Biol. Chem. 278:5509-5512(2003). RN [6] RP FUNCTION. RX PubMed=12527755; DOI=10.1074/jbc.c200651200; RA Girardin S.E., Boneca I.G., Viala J., Chamaillard M., Labigne A., RA Thomas G., Philpott D.J., Sansonetti P.J.; RT "Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) RT detection."; RL J. Biol. Chem. 278:8869-8872(2003). RN [7] RP FUNCTION. RX PubMed=12871942; DOI=10.1074/jbc.m307198200; RA Girardin S.E., Travassos L.H., Herve M., Blanot D., Boneca I.G., RA Philpott D.J., Sansonetti P.J., Mengin-Lecreulx D.; RT "Peptidoglycan molecular requirements allowing detection by Nod1 and RT Nod2."; RL J. Biol. Chem. 278:41702-41708(2003). RN [8] RP FUNCTION, VARIANTS BLAUS GLN-334; TRP-334 AND PHE-469, VARIANTS IBD1 RP TRP-702; VAL-863 AND 1007-LEU--LEU-1040 DELINS PRO, CHARACTERIZATION OF RP VARIANTS BLAUS GLN-334; TRP-334 AND PHE-469, AND CHARACTERIZATION OF RP VARIANTS IBD1 TRP-702; VAL-863 AND 1007-LEU--LEU-1040 DELINS PRO. RX PubMed=12626759; DOI=10.1073/pnas.0530276100; RA Chamaillard M., Philpott D., Girardin S.E., Zouali H., Lesage S., RA Chareyre F., Bui T.H., Giovannini M., Zaehringer U., Penard-Lacronique V., RA Sansonetti P.J., Hugot J.P., Thomas G.; RT "Gene-environment interaction modulated by allelic heterogeneity in RT inflammatory diseases."; RL Proc. Natl. Acad. Sci. U.S.A. 100:3455-3460(2003). RN [9] RP FUNCTION, INTERACTION WITH RIPK2, AND MUTAGENESIS OF GLN-31; GLU-69; RP THR-91; ALA-106; LEU-145; MET-152; PRO-177; ARG-180; ALA-232; VAL-295; RP PHE-327; CYS-333; SER-344; ASP-379; SER-396; THR-401; PHE-408; ALA-429; RP VAL-492; LEU-626; ASN-637; PRO-639; LYS-655; PRO-668; ILE-673; GLY-680; RP LEU-690; ALA-691; CYS-710; SER-714; PHE-719; ALA-725; LYS-731; HIS-734; RP GLY-761; LEU-762; VAL-793; ILE-805; PRO-812; ASP-824; ALA-860; LEU-876; RP GLN-889; LEU-891; ALA-892; LEU-904; ASP-913; ALA-920; ALA-944; LEU-947; RP LEU-949; MET-956; GLN-968; GLY-978; SER-984; LYS-986 AND ALA-1002. RX PubMed=15044951; DOI=10.1038/sj.emboj.7600175; RA Tanabe T., Chamaillard M., Ogura Y., Zhu L., Qiu S., Masumoto J., Ghosh P., RA Moran A., Predergast M.M., Tromp G., Williams C.J., Inohara N., Nunez G.; RT "Regulatory regions and critical residues of NOD2 involved in muramyl RT dipeptide recognition."; RL EMBO J. 23:1587-1597(2004). RN [10] RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT IBD1 RP 1007-LEU--LEU-1040 DELINS PRO, AND MUTAGENESIS OF 1017-TRP--ARG-1019; RP TRP-1017; LEU-1018; ARG-1019 AND 1039-LEU-LEU-1040. RX PubMed=15998797; DOI=10.1083/jcb.200502153; RA Barnich N., Aguirre J.E., Reinecker H.C., Xavier R., Podolsky D.K.; RT "Membrane recruitment of NOD2 in intestinal epithelial cells is essential RT for nuclear factor-{kappa}B activation in muramyl dipeptide recognition."; RL J. Cell Biol. 170:21-26(2005). RN [11] RP INTERACTION WITH ERBIN, AND SUBCELLULAR LOCATION. RX PubMed=16203728; DOI=10.1074/jbc.m508538200; RA McDonald C., Chen F.F., Ollendorff V., Ogura Y., Marchetto S., Lecine P., RA 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 [12] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RIPK2. RX PubMed=17355968; DOI=10.1074/jbc.m606242200; RA Lecine P., Esmiol S., Metais J.Y., Nicoletti C., Nourry C., McDonald C., RA Nunez G., Hugot J.P., Borg J.P., Ollendorff V.; RT "The NOD2-RICK complex signals from the plasma membrane."; RL J. Biol. Chem. 282:15197-15207(2007). RN [13] 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., Humke E.W., RA Eckmann L., Powell J.J., Nizet V., Dixit V.M., Karin M.; RT "A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in RT response to Bacillus anthracis infection and muramyl dipeptide."; RL Proc. Natl. Acad. Sci. U.S.A. 105:7803-7808(2008). RN [14] 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 [15] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MAVS. RX PubMed=19701189; DOI=10.1038/ni.1782; RA Sabbah A., Chang T.H., Harnack R., Frohlich V., Tominaga K., Dube P.H., RA Xiang Y., Bose S.; RT "Activation of innate immune antiviral responses by Nod2."; RL Nat. Immunol. 10:1073-1080(2009). RN [16] RP FUNCTION, AND INTERACTION WITH ATG16L1. RX PubMed=20637199; DOI=10.1053/j.gastro.2010.07.006; RA Homer C.R., Richmond A.L., Rebert N.A., Achkar J.P., McDonald C.; RT "ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway RT implicated in Crohn's disease pathogenesis."; RL Gastroenterology 139:1630-1641(2010). RN [17] RP IDENTIFICATION IN A COMPLEX WITH ARHGEF2 AND RIPK2, AND INTERACTION WITH RP 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-H1."; RL Inflamm. Bowel Dis. 18:603-612(2012). RN [18] RP FUNCTION. RX PubMed=22857257; DOI=10.1021/ja303883c; RA Grimes C.L., Ariyananda L.D.Z., Melnyk J.E., O'Shea E.K.; RT "The innate immune protein Nod2 binds directly to MDP, a bacterial cell RT wall fragment."; RL J. Am. Chem. Soc. 134:13535-13537(2012). RN [19] RP TISSUE SPECIFICITY, SUBUNIT, AND INTERACTION WITH MAPKBP1. RX PubMed=22700971; DOI=10.1074/jbc.m112.355545; RA Lecat A., Di Valentin E., Somja J., Jourdan S., Fillet M., Kufer T.A., RA Habraken Y., Sadzot C., Louis E., Delvenne P., Piette J., Legrand-Poels S.; RT "The c-Jun N-terminal kinase (JNK)-binding protein (JNKBP1) acts as a RT negative regulator of NOD2 protein signaling by inhibiting its RT oligomerization process."; RL J. Biol. Chem. 287:29213-29226(2012). RN [20] RP INTERACTION WITH HSP90 AND SOCS3, AND POLYUBIQUITINATION. RX PubMed=23019338; DOI=10.1074/jbc.m112.410027; RA Lee K.H., Biswas A., Liu Y.J., Kobayashi K.S.; RT "Proteasomal degradation of Nod2 protein mediates tolerance to bacterial RT cell wall components."; RL J. Biol. Chem. 287:39800-39811(2012). RN [21] RP UBIQUITINATION BY TRIM27. RX PubMed=22829933; DOI=10.1371/journal.pone.0041255; RA Zurek B., Schoultz I., Neerincx A., Napolitano L.M., Birkner K., Bennek E., RA Sellge G., Lerm M., Meroni G., Soederholm J.D., Kufer T.A.; RT "TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal RT degradation."; RL PLoS ONE 7:e41255-e41255(2012). RN [22] RP INTERACTION WITH ATG16L1. RX PubMed=23376921; DOI=10.1038/emboj.2013.8; RA Boada-Romero E., Letek M., Fleischer A., Pallauf K., Ramon-Barros C., RA Pimentel-Muinos F.X.; RT "TMEM59 defines a novel ATG16L1-binding motif that promotes local RT activation of LC3."; RL EMBO J. 32:566-582(2013). RN [23] RP INTERACTION WITH ANKRD17. RX PubMed=23711367; DOI=10.1016/j.febslet.2013.05.037; RA Menning M., Kufer T.A.; RT "A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and RT Nod2-mediated inflammatory responses."; RL FEBS Lett. 587:2137-2142(2013). RN [24] RP FUNCTION. RX PubMed=23806334; DOI=10.1016/j.molcel.2013.06.004; RA Fiil B.K., Damgaard R.B., Wagner S.A., Keusekotten K., Fritsch M., RA Bekker-Jensen S., Mailand N., Choudhary C., Komander D., Gyrd-Hansen M.; RT "OTULIN restricts Met1-linked ubiquitination to control innate immune RT signaling."; RL Mol. Cell 50:818-830(2013). RN [25] RP FUNCTION. RX PubMed=23322906; DOI=10.1126/scisignal.2003305; RA Warner N., Burberry A., Franchi L., Kim Y.G., McDonald C., Sartor M.A., RA Nunez G.; RT "A genome-wide siRNA screen reveals positive and negative regulators of the RT NOD2 and NF-kappaB signaling pathways."; RL Sci. Signal. 6:rs3-rs3(2013). RN [26] RP INTERACTION WITH CARD9, VARIANTS IBD1 ALA-357; PHE-363 AND VAL-550, VARIANT RP ALA-463, CHARACTERIZATION OF VARIANTS IBD1 ARG-248; ALA-357; PHE-363; RP LEU-431; LYS-441; VAL-550; VAL-612 AND TRP-702, CHARACTERIZATION OF VARIANT RP BLAUS TRP-334, CHARACTERIZATION OF VARIANT ALA-463, AND MUTAGENESIS OF RP ASP-379. RX PubMed=24960071; DOI=10.1016/j.febslet.2014.06.035; RA Parkhouse R., Boyle J.P., Mayle S., Sawmynaden K., Rittinger K., RA Monie T.P.; RT "Interaction between NOD2 and CARD9 involves the NOD2 NACHT and the linker RT region between the NOD2 CARDs and NACHT domain."; RL FEBS Lett. 588:2830-2836(2014). RN [27] RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS BLAUS GLN-334; TRP-334; RP GLY-383; LYS-383; PHE-469; ASP-481; LEU-490; TYR-495; LEU-496; THR-513; RP CYS-587; ASN-605; PRO-605 AND LYS-670, AND CHARACTERIZATION OF VARIANTS AND RP CYS-471. RX PubMed=25093298; DOI=10.1016/j.febslet.2014.07.029; RA Parkhouse R., Boyle J.P., Monie T.P.; RT "Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and RT helical domain 1 as signalling regulators."; RL FEBS Lett. 588:3382-3389(2014). RN [28] RP INTERACTION WITH HSPA1A, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF RP VARIANTS IBD1 TRP-702 AND ARG-908. RX PubMed=24790089; DOI=10.1074/jbc.m114.557686; RA Mohanan V., Grimes C.L.; RT "The molecular chaperone HSP70 binds to and stabilizes NOD2, an important RT protein involved in Crohn disease."; RL J. Biol. Chem. 289:18987-18998(2014). RN [29] RP INTERACTION WITH IRGM. RX PubMed=25891078; DOI=10.1016/j.molcel.2015.03.020; RA Chauhan S., Mandell M.A., Deretic V.; RT "IRGM governs the core autophagy machinery to conduct antimicrobial RT defense."; RL Mol. Cell 58:507-521(2015). RN [30] RP GLYCOSYLATION. RX PubMed=26369908; DOI=10.1093/glycob/cwv076; RA Hou C.W., Mohanan V., Zachara N.E., Grimes C.L.; RT "Identification and biological consequences of the O-GlcNAc modification of RT the human innate immune receptor, Nod2."; RL Glycobiology 26:13-18(2016). RN [31] RP FUNCTION, AND INTERACTION WITH RIPK2. RX PubMed=27007849; DOI=10.1038/nature17631; RA Keestra-Gounder A.M., Byndloss M.X., Seyffert N., Young B.M., RA Chavez-Arroyo A., Tsai A.Y., Cevallos S.A., Winter M.G., Pham O.H., RA Tiffany C.R., de Jong M.F., Kerrinnes T., Ravindran R., Luciw P.A., RA McSorley S.J., Baeumler A.J., Tsolis R.M.; RT "NOD1 and NOD2 signalling links ER stress with inflammation."; RL Nature 532:394-397(2016). RN [32] RP FUNCTION, AND MUTAGENESIS OF ARG-334; ARG-426; GLY-481; GLU-600; HIS-603; RP ASN-670; TYR-799; ARG-823; ASP-824; PHE-851; ASN-852; ARG-877; GLY-905; RP TRP-907; TRP-931; SER-933; VAL-935; GLY-936; CYS-961; GLU-964 AND ASN-992. RX PubMed=27283905; DOI=10.1038/ncomms11813; RA Maekawa S., Ohto U., Shibata T., Miyake K., Shimizu T.; RT "Crystal structure of NOD2 and its implications in human disease."; RL Nat. Commun. 7:11813-11813(2016). RN [33] RP INTERACTION WITH ANKHD1; C10ORF67; CHMP5; DOCK7; ENTR1; KRT15; LDOC1; RP PPP1R12C; PPP2R3B; RIPK2; TRIM41 AND VIM, INDUCTION, CHARACTERIZATION OF RP VARIANTS IBD1 TRP-702 AND ARG-908, AND CHARACTERIZATION OF VARIANT BLAUS RP GLN-334. RX PubMed=27812135; DOI=10.1371/journal.pone.0165420; RA Thiebaut R., Esmiol S., Lecine P., Mahfouz B., Hermant A., Nicoletti C., RA Parnis S., Perroy J., Borg J.P., Pascoe L., Hugot J.P., Ollendorff V.; RT "Characterization and Genetic Analyses of New Genes Coding for NOD2 RT Interacting Proteins."; RL PLoS ONE 11:E0165420-E0165420(2016). RN [34] RP FUNCTION, DOMAIN, AND MUTAGENESIS OF ARG-877; TRP-931 AND SER-933. RX PubMed=27748583; DOI=10.1021/acsinfecdis.6b00154; RA Lauro M.L., D'Ambrosio E.A., Bahnson B.J., Grimes C.L.; RT "Molecular recognition of muramyl dipeptide occurs in the leucine-rich RT repeat domain of Nod2."; RL ACS Infect. Dis. 3:264-270(2017). RN [35] RP UBIQUITIN-BINDING, INTERACTION WITH RIPK2, AND MUTAGENESIS OF ILE-104 AND RP LEU-200. RX PubMed=23300079; DOI=10.1074/jbc.m112.413781; RA Ver Heul A.M., Fowler C.A., Ramaswamy S., Piper R.C.; RT "Ubiquitin regulates caspase recruitment domain-mediated signaling by RT nucleotide-binding oligomerization domain-containing proteins NOD1 and RT NOD2."; RL J. Biol. Chem. 288:6890-6902(2013). RN [36] RP FUNCTION, AND INTERACTION WITH INAVA. RX PubMed=28436939; DOI=10.1172/jci86282; RA Yan J., Hedl M., Abraham C.; RT "An inflammatory bowel disease-risk variant in INAVA decreases pattern RT recognition receptor-induced outcomes."; RL J. Clin. Invest. 127:2192-2205(2017). RN [37] RP INTERACTION WITH RIPK2. RX PubMed=30279485; DOI=10.1038/s41467-018-06451-3; RA Pellegrini E., Desfosses A., Wallmann A., Schulze W.M., Rehbein K., Mas P., RA Signor L., Gaudon S., Zenkeviciute G., Hons M., Malet H., Gutsche I., RA Sachse C., Schoehn G., Oschkinat H., Cusack S.; RT "RIP2 filament formation is required for NOD2 dependent NF-kappaB RT signalling."; RL Nat. Commun. 9:4043-4043(2018). RN [38] RP INTERACTION WITH RIPK2. RX PubMed=30478312; DOI=10.1038/s41467-018-07447-9; RA Gong Q., Long Z., Zhong F.L., Teo D.E.T., Jin Y., Yin Z., Boo Z.Z., RA Zhang Y., Zhang J., Yang R., Bhushan S., Reversade B., Li Z., Wu B.; RT "Structural basis of RIP2 activation and signaling."; RL Nat. Commun. 9:4993-4993(2018). RN [39] RP INTERACTION WITH NLRP12. RX PubMed=30559449; DOI=10.1038/s41467-018-07750-5; RA Normand S., Waldschmitt N., Neerincx A., Martinez-Torres R.J., Chauvin C., RA Couturier-Maillard A., Boulard O., Cobret L., Awad F., Huot L., RA Ribeiro-Ribeiro A., Lautz K., Ruez R., Delacre M., Bondu C., Guilliams M., RA Scott C., Segal A., Amselem S., Hot D., Karabina S., Bohn E., Ryffel B., RA Poulin L.F., Kufer T.A., Chamaillard M.; RT "Proteasomal degradation of NOD2 by NLRP12 in monocytes promotes bacterial RT tolerance and colonization by enteropathogens."; RL Nat. Commun. 9:5338-5338(2018). RN [40] RP FUNCTION, PALMITOYLATION AT CYS-395 AND CYS-1033, MUTAGENESIS OF CYS-395 RP AND CYS-1033, AND SUBCELLULAR LOCATION. RX PubMed=31649195; DOI=10.1126/science.aau6391; RA Lu Y., Zheng Y., Coyaud E., Zhang C., Selvabaskaran A., Yu Y., Xu Z., RA Weng X., Chen J.S., Meng Y., Warner N., Cheng X., Liu Y., Yao B., Hu H., RA Xia Z., Muise A.M., Klip A., Brumell J.H., Girardin S.E., Ying S., RA Fairn G.D., Raught B., Sun Q., Neculai D.; RT "Palmitoylation of NOD1 and NOD2 is required for bacterial sensing."; RL Science 366:460-467(2019). RN [41] RP FUNCTION, AND DOMAIN. RX PubMed=33942347; DOI=10.15252/embj.2020106272; RA Pei G., Zyla J., He L., Moura-Alves P., Steinle H., Saikali P., Lozza L., RA Nieuwenhuizen N., Weiner J., Mollenkopf H.J., Ellwanger K., Arnold C., RA Duan M., Dagil Y., Pashenkov M., Boneca I.G., Kufer T.A., Dorhoi A., RA Kaufmann S.H.; RT "Cellular stress promotes NOD1/2-dependent inflammation via the endogenous RT metabolite sphingosine-1-phosphate."; RL EMBO J. 40:e106272-e106272(2021). RN [42] RP SUBCELLULAR LOCATION, PALMITOYLATION AT CYS-395 AND CYS-1033, AND RP MUTAGENESIS OF CYS-395 AND CYS-1033. RX PubMed=34293401; DOI=10.1016/j.jlr.2021.100097; RA Dixon C.L., Fairn G.D.; RT "S-palmitoylation of NOD2 controls its localization to the plasma RT membrane."; RL J. Lipid Res. 62:100097-100097(2021). RN [43] RP PALMITOYLATION AT CYS-395 AND CYS-1033, PROTEIN DEGRADATION, VARIANT RP CYS-444 (ISOFORM 2), MUTAGENESIS OF CYS-395 AND CYS-1033, AND RP CHARACTERIZATION OF VARIANT CYS-444 (ISOFORM 2). RX PubMed=35066577; DOI=10.1038/s41418-022-00942-z; RA Zhou L., He X., Wang L., Wei P., Cai Z., Zhang S., Jin S., Zeng H., Cui J.; RT "Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of RT NOD2 to modulate inflammation."; RL Cell Death Differ. 29:1541-1551(2022). RN [44] RP INTERACTION WITH IRGM, AND PROTEIN DEGRADATION. RX PubMed=36221902; DOI=10.15252/embj.2022111289; RA Mehto S., Jena K.K., Yadav R., Priyadarsini S., Samal P., Krishna S., RA Dhar K., Jain A., Chauhan N.R., Murmu K.C., Bal R., Sahu R., Jaiswal P., RA Sahoo B.S., Patnaik S., Kufer T.A., Rusten T.E., Chauhan S., Prasad P., RA Chauhan S.; RT "Selective autophagy of RIPosomes maintains innate immune homeostasis RT during bacterial infection."; RL EMBO J. 41:e111289-e111289(2022). RN [45] RP FUNCTION. RX PubMed=36002575; DOI=10.1038/s41586-022-05125-x; RA Stafford C.A., Gassauer A.M., de Oliveira Mann C.C., Tanzer M.C., RA Fessler E., Wefers B., Nagl D., Kuut G., Sulek K., Vasilopoulou C., RA Schwojer S.J., Wiest A., Pfautsch M.K., Wurst W., Yabal M., Froehlich T., RA Mann M., Gisch N., Jae L.T., Hornung V.; RT "Phosphorylation of muramyl peptides by NAGK is required for NOD2 RT activation."; RL Nature 609:590-596(2022). RN [46] RP VARIANT IBD1 1007-LEU--LEU-1040 DELINS PRO. RX PubMed=11385577; DOI=10.1038/35079114; RA Ogura Y., Bonen D.K., Inohara N., Nicolae D.L., Chen F.F., Ramos R., RA Britton H., Moran T., Karaliuskas R., Duerr R.H., Achkar J.P., Brant S.R., RA Bayless T.M., Kirschner B.S., Hanauer S.B., Nunez G., Cho J.H.; RT "A frameshift mutation in NOD2 associated with susceptibility to Crohn's RT disease."; RL Nature 411:603-606(2001). RN [47] RP VARIANTS BLAUS GLN-334; TRP-334 AND PHE-469. RX PubMed=11528384; DOI=10.1038/ng720; RA Miceli-Richard C., Lesage S., Rybojad M., Prieur A.M., Manouvrier-Hanu S., RA Hafner R., Chamaillard M., Zouali H., Thomas G., Hugot J.-P.; RT "CARD15 mutations in Blau syndrome."; RL Nat. Genet. 29:19-20(2001). RN [48] RP VARIANTS IBD1 ASN-113; ALA-357; PHE-363; VAL-550 AND SER-852. RX PubMed=15024686; DOI=10.1086/382226; RA Tukel T., Shalata A., Present D., Rachmilewitz D., Mayer L., Grant D., RA Risch N., Desnick R.J.; RT "Crohn disease: frequency and nature of CARD15 mutations in Ashkenazi and RT Sephardi/Oriental Jewish families."; RL Am. J. Hum. Genet. 74:623-636(2004). RN [49] RP VARIANTS IBD1 TRP-702; ARG-908 AND 1007-LEU--LEU-1040 DELINS PRO, RP CHARACTERIZATION OF VARIANTS IBD1 TRP-702; ARG-908 AND 1007-LEU--LEU-1040 RP DELINS PRO, AND FUNCTION. RX PubMed=15198989; DOI=10.1093/hmg/ddh182; RA Li J., Moran T., Swanson E., Julian C., Harris J., Bonen D.K., Hedl M., RA Nicolae D.L., Abraham C., Cho J.H.; RT "Regulation of IL-8 and IL-1beta expression in Crohn's disease associated RT NOD2/CARD15 mutations."; RL Hum. Mol. Genet. 13:1715-1725(2004). RN [50] RP VARIANTS BLAUS TRP-334; GLU-382; LEU-496; THR-513; PRO-605; THR-612 AND RP LYS-670, AND CHARACTERIZATION OF VARIANTS BLAUS GLU-382; LEU-496; THR-513; RP PRO-605 AND LYS-670. RX PubMed=15459013; DOI=10.1182/blood-2004-07-2972; RA Kanazawa N., Okafuji I., Kambe N., Nishikomori R., Nakata-Hizume M., RA Nagai S., Fuji A., Yuasa T., Manki A., Sakurai Y., Nakajima M., RA Kobayashi H., Fujiwara I., Tsutsumi H., Utani A., Nishigori C., Heike T., RA Nakahata T., Miyachi Y.; RT "Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear RT factor-kappaB activation: common genetic etiology with Blau syndrome."; RL Blood 105:1195-1197(2005). RN [51] RP VARIANT BLAUS LYS-383. RX PubMed=15812565; DOI=10.1038/sj.ejhg.5201404; RA van Duist M.M., Albrecht M., Podswiadek M., Giachino D., Lengauer T., RA Punzi L., De Marchi M.; RT "A new CARD15 mutation in Blau syndrome."; RL Eur. J. Hum. Genet. 13:742-747(2005). RN [52] RP VARIANTS IBD1 TRP-311; TRP-702; CYS-703; HIS-713; VAL-755; CYS-760; TRP-790 RP AND ARG-908, AND VARIANTS SER-268; SER-289; CYS-391; ALA-463; TRP-791; RP LYS-825 AND VAL-849. RX PubMed=16485124; DOI=10.1007/s00251-005-0073-2; RA Schnitzler F., Brand S., Staudinger T., Pfennig S., Hofbauer K., RA Seiderer J., Tillack C., Goke B., Ochsenkuhn T., Lohse P.; RT "Eight novel CARD15 variants detected by DNA sequence analysis of the RT CARD15 gene in 111 patients with inflammatory bowel disease."; RL Immunogenetics 58:99-106(2006). RN [53] RP VARIANTS BLAUS GLN-334; TRP-334; LYS-383; LEU-490; TYR-495 AND CYS-587. RX PubMed=19479837; DOI=10.1002/art.24533; RA Rose C.D., Arostegui J.I., Martin T.M., Espada G., Scalzi L., Yague J., RA Rosenbaum J.T., Modesto C., Cristina Arnal M., Merino R., RA Garcia-Consuegra J., Carballo Silva M.A., Wouters C.H.; RT "NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: RT study of an international registry and a national cohort in Spain."; RL Arthritis Rheum. 60:1797-1803(2009). RN [54] RP VARIANTS BLAUS GLN-334; TRP-334; GLU-382; GLY-383; TYR-495; LEU-496; RP THR-513; PRO-605 AND LYS-670. RX PubMed=19116920; DOI=10.1002/art.24134; RA Okafuji I., Nishikomori R., Kanazawa N., Kambe N., Fujisawa A., RA Yamazaki S., Saito M., Yoshioka T., Kawai T., Sakai H., Tanizaki H., RA Heike T., Miyachi Y., Nakahata T.; RT "Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and RT early-onset sarcoidosis."; RL Arthritis Rheum. 60:242-250(2009). RN [55] RP VARIANT BLAUS ASP-481. RX PubMed=19359344; DOI=10.1093/rheumatology/kep061; RA Okada S., Konishi N., Tsumura M., Shirao K., Yasunaga S., Sakai H., RA Nishikomori R., Takihara Y., Kobayashi M.; RT "Cardiac infiltration in early-onset sarcoidosis associated with a novel RT heterozygous mutation, G481D, in CARD15."; RL Rheumatology 48:706-707(2009). RN [56] RP VARIANT BLAUS ASN-605. RX PubMed=19169908; DOI=10.1080/03009740802464194; RA Milman N., Ursin K., Rodevand E., Nielsen F.C., Hansen T.V.; RT "A novel mutation in the NOD2 gene associated with Blau syndrome: a RT Norwegian family with four affected members."; RL Scand. J. Rheumatol. 38:190-197(2009). RN [57] RP VARIANT BLAUS TRP-334. RX PubMed=20199415; DOI=10.1111/j.1525-1470.2009.01060.x; RA Stoevesandt J., Morbach H., Martin T.M., Zierhut M., Girschick H., Hamm H.; RT "Sporadic Blau syndrome with onset of widespread granulomatous dermatitis RT in the newborn period."; RL Pediatr. Dermatol. 27:69-73(2010). RN [58] RP INVOLVEMENT IN YAOS, AND VARIANT YAOS TRP-702. RX PubMed=21914217; DOI=10.1186/ar3462; RA Yao Q., Zhou L., Cusumano P., Bose N., Piliang M., Jayakar B., Su L.C., RA Shen B.; RT "A new category of autoinflammatory disease associated with NOD2 gene RT mutations."; RL Arthritis Res. Ther. 13:R148-R148(2011). RN [59] RP VARIANT BLAUS SER-507. RX PubMed=25692065; DOI=10.1155/2015/463959; RA Zeybek C., Basbozkurt G., Gul D., Demirkaya E., Gok F.; RT "A new mutation in blau syndrome."; RL Case Rep. Rheumatol. 2015:463959-463959(2015). RN [60] RP VARIANT BLAUS GLN-334, AND VARIANT SER-268. RX PubMed=25724124; DOI=10.1016/j.jaci.2014.12.1941; RA de Inocencio J., Mensa-Vilaro A., Tejada-Palacios P., Enriquez-Merayo E., RA Gonzalez-Roca E., Magri G., Ruiz-Ortiz E., Cerutti A., Yaguee J., RA Arostegui J.I.; RT "Somatic NOD2 mosaicism in Blau syndrome."; RL J. Allergy Clin. Immunol. 0:0-0(2015). RN [61] RP INVOLVEMENT IN YAOS, AND VARIANT YAOS ARG-908. RX PubMed=26070941; DOI=10.1093/rheumatology/kev207; RA Yao Q., Shen M., McDonald C., Lacbawan F., Moran R., Shen B.; RT "NOD2-associated autoinflammatory disease: a large cohort study."; RL Rheumatology 54:1904-1912(2015). RN [62] RP VARIANT BLAUS ASP-498. RX PubMed=34251956; DOI=10.1080/13816810.2021.1946701; RA Rodrigues F.G., Petrushkin H., Webster A.R., Bickerstaff M., Moraitis E., RA Rowczenio D., Arostegui J.I., Westcott M.; RT "A novel pathogenic NOD2 variant in a mother and daughter with Blau RT syndrome."; RL Ophthalmic Genet. 42:753-764(2021). CC -!- FUNCTION: Pattern recognition receptor (PRR) that detects bacterial CC peptidoglycan fragments and other danger signals and plays an important CC role in gastrointestinal immunity (PubMed:12514169, PubMed:12527755, CC PubMed:12626759, PubMed:15044951, PubMed:15998797, PubMed:27283905, CC PubMed:27748583, PubMed:31649195). Specifically activated by muramyl CC dipeptide (MDP), a fragment of bacterial peptidoglycan found in every CC bacterial peptidoglycan type (PubMed:12514169, PubMed:12871942, CC PubMed:12527755, PubMed:12626759, PubMed:15044951, PubMed:15998797, CC PubMed:22857257, PubMed:23322906, PubMed:27748583, PubMed:36002575, CC PubMed:15198989). NOD2 specifically recognizes and binds 6-O-phospho- CC MDP, the phosphorylated form of MDP, which is generated by NAGK CC (PubMed:36002575). 6-O-phospho-MDP-binding triggers oligomerization CC that facilitates the binding and subsequent activation of the proximal CC adapter receptor-interacting RIPK2 (PubMed:11087742, PubMed:17355968, CC PubMed:21887730, PubMed:23806334, PubMed:28436939). Following CC recruitment, RIPK2 undergoes 'Met-1'- (linear) and 'Lys-63'-linked CC polyubiquitination by E3 ubiquitin-protein ligases XIAP, BIRC2, BIRC3 CC and the LUBAC complex, becoming a scaffolding protein for downstream CC effectors, triggering activation of the NF-kappa-B and MAP kinases CC signaling (PubMed:11087742, PubMed:12514169, PubMed:12626759, CC PubMed:21887730, PubMed:23806334, PubMed:23322906, PubMed:28436939, CC PubMed:15198989). This in turn leads to the transcriptional activation CC of hundreds of genes involved in immune response (PubMed:15198989). Its CC ability to detect bacterial MDP plays a central role in maintaining the CC equilibrium between intestinal microbiota and host immune responses to CC control inflammation (By similarity). An imbalance in this relationship CC results in dysbiosis, whereby pathogenic bacteria prevail on CC commensals, causing damage in the intestinal epithelial barrier as well CC as allowing bacterial invasion and inflammation (By similarity). Acts CC as a regulator of appetite by sensing MDP in a subset of brain neurons: CC microbiota-derived MDP reach the brain, where they bind and activate CC NOD2 in inhibitory hypothalamic neurons, decreasing neuronal activity, CC thereby regulating satiety and body temperature (By similarity). NOD2- CC dependent MDP-sensing of bacterial cell walls in the intestinal CC epithelial compartment contributes to sustained postnatal growth upon CC undernutrition (By similarity). Also plays a role in antiviral response CC by acting as a sensor of single-stranded RNA (ssRNA) from viruses: upon CC ssRNA-binding, interacts with MAVS, leading to activation of interferon CC regulatory factor-3/IRF3 and expression of type I interferon CC (PubMed:19701189). Also acts as a regulator of autophagy in dendritic CC cells via its interaction with ATG16L1, possibly by recruiting ATG16L1 CC at the site of bacterial entry (PubMed:20637199). NOD2 activation in CC the small intestine crypt also contributes to intestinal stem cells CC survival and function: acts by promoting mitophagy via its association CC with ATG16L1 (By similarity). In addition to its main role in innate CC immunity, also regulates the adaptive immune system by acting as CC regulator of helper T-cell and regulatory T-cells (Tregs) (By CC similarity). Besides recognizing pathogens, also involved in the CC endoplasmic reticulum stress response: acts by sensing and binding to CC the cytosolic metabolite sphingosine-1-phosphate generated in response CC to endoplasmic reticulum stress, initiating an inflammation process CC that leads to activation of the NF-kappa-B and MAP kinases signaling CC (PubMed:27007849, PubMed:33942347). May also be involved in NLRP1 CC activation following activation by MDP, leading to CASP1 activation and CC IL1B release in macrophages (PubMed:18511561). CC {ECO:0000250|UniProtKB:Q8K3Z0, ECO:0000269|PubMed:11087742, CC ECO:0000269|PubMed:12514169, ECO:0000269|PubMed:12527755, CC ECO:0000269|PubMed:12626759, ECO:0000269|PubMed:12871942, CC ECO:0000269|PubMed:15044951, ECO:0000269|PubMed:15198989, CC ECO:0000269|PubMed:15998797, ECO:0000269|PubMed:17355968, CC ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:19701189, CC ECO:0000269|PubMed:20637199, ECO:0000269|PubMed:21887730, CC ECO:0000269|PubMed:22857257, ECO:0000269|PubMed:23322906, CC ECO:0000269|PubMed:23806334, ECO:0000269|PubMed:27007849, CC ECO:0000269|PubMed:27283905, ECO:0000269|PubMed:27748583, CC ECO:0000269|PubMed:28436939, ECO:0000269|PubMed:31649195, CC ECO:0000269|PubMed:33942347, ECO:0000269|PubMed:36002575}. CC -!- FUNCTION: [Isoform 2]: Acts as a pattern recognition receptor (PRR); CC able to activate NF-kappa-B. {ECO:0000269|PubMed:11087742}. CC -!- FUNCTION: [Isoform 3]: Can activate NF-kappa-B in a muramyl dipeptide CC (MDP)-independent manner. {ECO:0000269|PubMed:20698950}. CC -!- ACTIVITY REGULATION: ADP-binding promotes an inactive closed CC conformation. {ECO:0000250|UniProtKB:G1T469}. CC -!- SUBUNIT: Homooligomer: homooligomerizes following muramyl dipeptide CC (MDP)-binding, promoting RIPK2 recruitment (PubMed:11087742, CC PubMed:22700971). Interacts (via CARD domain) with RIPK2 (via CARD CC domain) (PubMed:11087742, PubMed:15044951, PubMed:17355968, CC PubMed:19592251, PubMed:27812135, PubMed:30279485, PubMed:30478312). CC Following RIPK2 recruitment, RIPK2 homooligomerizes via its CARD domain CC and forms long filaments named RIPosomes (PubMed:30279485, CC PubMed:30478312). Interacts (via CARD domain) with ubiquitin; CC inhibiting interaction with RIPK2 (PubMed:23300079). Component of a CC signaling complex consisting of ARHGEF2, NOD2 and RIPK2 CC (PubMed:21887730). Interacts with ANKRD17 (via N-terminus) CC (PubMed:23711367). Interacts with HSPA1A; the interaction enhances NOD2 CC stability (PubMed:24790089). Interacts (via both CARD domains) with CC HSP90; the interaction enhances NOD2 stability (PubMed:23019338). CC Interacts (via CARD domain) with SOCS3; the interaction promotes NOD2 CC degradation (PubMed:23019338). Interacts (via CARD domain) with ERBIN; CC the interaction inhibits activation of NOD2 (PubMed:16203728). CC Interacts with MAPKBP1; the interaction is enhanced in the presence of CC muramyl dipeptide (MDP) and inhibits NOD2 homooligomerization and CC activation (PubMed:22700971). Interacts with INAVA; the interaction CC takes place upon Pattern recognition receptor (PRR) stimulation CC (PubMed:28436939). Interacts (via NACHT domain) with CARD9 CC (PubMed:24960071). Interacts (via CARD domain) with CASP1; this CC interaction leads to IL1B processing (PubMed:18511561). Also interacts CC with CASP4 (PubMed:18511561). Interacts with NLRP1; this interaction is CC enhanced in the presence of muramyl dipeptide (MDP) and leads to CC increased IL1B release (PubMed:18511561). Interacts with NLRP12; this CC interaction promotes degradation of NOD2 through the ubiquitin- CC proteasome pathway (PubMed:30559449). Interacts with ANKHD1, C10orf67, CC CHMP5, DOCK7, ENTR1, KRT15, LDOC1, PPP1R12C, PPP2R3B, TRIM41 and VIM CC (PubMed:27812135). Interacts with MAVS; interaction takes place CC following single-stranded RNA (ssRNA)-binding (PubMed:19701189). CC Interacts with ATG16L1 (PubMed:20637199, PubMed:23376921). Interacts CC with IRGM; promoting IRGM 'Lys-63'-linked polyubiquitination, which is CC required for interactions with the core autophagy factors CC (PubMed:25891078, PubMed:36221902). {ECO:0000269|PubMed:11087742, CC ECO:0000269|PubMed:15044951, ECO:0000269|PubMed:16203728, CC ECO:0000269|PubMed:17355968, ECO:0000269|PubMed:18511561, CC ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19701189, CC ECO:0000269|PubMed:20637199, ECO:0000269|PubMed:21887730, CC ECO:0000269|PubMed:22700971, ECO:0000269|PubMed:23019338, CC ECO:0000269|PubMed:23300079, ECO:0000269|PubMed:23376921, CC ECO:0000269|PubMed:23711367, ECO:0000269|PubMed:24790089, CC ECO:0000269|PubMed:24960071, ECO:0000269|PubMed:25891078, CC ECO:0000269|PubMed:27812135, ECO:0000269|PubMed:28436939, CC ECO:0000269|PubMed:30279485, ECO:0000269|PubMed:30478312, CC ECO:0000269|PubMed:30559449, ECO:0000269|PubMed:36221902}. CC -!- INTERACTION: CC Q9HC29; P29466: CASP1; NbExp=4; IntAct=EBI-7445625, EBI-516667; CC Q9HC29; Q96RT1: ERBIN; NbExp=5; IntAct=EBI-7445625, EBI-993903; CC Q9HC29; Q96RT1-2: ERBIN; NbExp=5; IntAct=EBI-7445625, EBI-8449250; CC Q9HC29; Q9Y3D6: FIS1; NbExp=2; IntAct=EBI-7445625, EBI-3385283; CC Q9HC29; Q10471: GALNT2; NbExp=2; IntAct=EBI-7445625, EBI-10226985; CC Q9HC29; Q92993: KAT5; NbExp=2; IntAct=EBI-7445625, EBI-399080; CC Q9HC29; Q9P0J0: NDUFA13; NbExp=6; IntAct=EBI-7445625, EBI-372742; CC Q9HC29; Q6UX06: OLFM4; NbExp=2; IntAct=EBI-7445625, EBI-2804156; CC Q9HC29; Q16537: PPP2R5E; NbExp=2; IntAct=EBI-7445625, EBI-968374; CC Q9HC29; O43353: RIPK2; NbExp=3; IntAct=EBI-7445625, EBI-358522; CC Q9HC29; Q8IY34: SLC15A3; NbExp=2; IntAct=EBI-7445625, EBI-12179023; CC Q9HC29; Q8N697: SLC15A4; NbExp=2; IntAct=EBI-7445625, EBI-4319594; CC Q9HC29; Q04724: TLE1; NbExp=2; IntAct=EBI-7445625, EBI-711424; CC Q9HC29; P14373: TRIM27; NbExp=10; IntAct=EBI-7445625, EBI-719493; CC Q9HC29; P08670: VIM; NbExp=7; IntAct=EBI-7445625, EBI-353844; CC Q9HC29-1; Q9UJY1: HSPB8; NbExp=2; IntAct=EBI-21496213, EBI-739074; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15998797, CC ECO:0000269|PubMed:25093298, ECO:0000269|PubMed:31649195, CC ECO:0000269|PubMed:34293401}; Lipid-anchor CC {ECO:0000269|PubMed:31649195, ECO:0000269|PubMed:34293401}. Basolateral CC cell membrane {ECO:0000269|PubMed:16203728, CC ECO:0000269|PubMed:17355968}. Cytoplasm {ECO:0000269|PubMed:14570728, CC ECO:0000269|PubMed:15998797, ECO:0000269|PubMed:19701189, CC ECO:0000269|PubMed:24790089, ECO:0000269|PubMed:25093298}. CC Mitochondrion {ECO:0000269|PubMed:19701189}. Note=Palmitoylation CC promotes localization to the cell membrane, where it detects bacterial CC invasion at the point of entry. {ECO:0000269|PubMed:34293401}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm CC {ECO:0000269|PubMed:20698950}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative initiation; Named isoforms=3; CC Name=1; Synonyms=Nod2 {ECO:0000303|PubMed:11087742}, NOD2L CC {ECO:0000303|PubMed:35066577}; CC IsoId=Q9HC29-1; Sequence=Displayed; CC Name=2; Synonyms=Nod2b {ECO:0000303|PubMed:11087742}, NOD2S CC {ECO:0000303|PubMed:35066577}; CC IsoId=Q9HC29-2; Sequence=VSP_018689; CC Name=3; Synonyms=NOD2-C2 {ECO:0000303|PubMed:20698950}; CC IsoId=Q9HC29-3; Sequence=VSP_018689, VSP_046567, VSP_046568; CC -!- TISSUE SPECIFICITY: Expressed in monocytes, macrophages, dendritic CC cells, hepatocytes, preadipocytes, epithelial cells of oral cavity, CC lung and intestine, with higher expression in ileal Paneth cells and in CC intestinal stem cells. {ECO:0000269|PubMed:11087742, CC ECO:0000269|PubMed:14570728, ECO:0000269|PubMed:22700971}. CC -!- TISSUE SPECIFICITY: [Isoform 3]: Expressed at higher level in CC leukocytes. {ECO:0000269|PubMed:20698950}. CC -!- INDUCTION: Up-regulated by muramyl-dipeptide and lipopolysaccharide. CC {ECO:0000269|PubMed:27812135}. CC -!- DOMAIN: The ATG16L1-binding motif mediates interaction with ATG16L1. CC {ECO:0000269|PubMed:23376921}. CC -!- DOMAIN: Intramolecular interactions between the N-terminal moiety and CC the leucine-rich repeats (LRR) may be important for autoinhibition in CC the absence of activating signal. {ECO:0000269|PubMed:18511561}. CC -!- DOMAIN: The LRR repeats recognize and bind muramyl dipeptide (MDP). CC {ECO:0000269|PubMed:27748583}. CC -!- DOMAIN: The NACHT domain recognizes and binds sphingosine-1-phosphate CC in response to endoplasmic reticulum stress. CC {ECO:0000269|PubMed:33942347}. CC -!- PTM: Palmitoylated by ZDHHC5; palmitoylation is required for proper CC recruitment to the bacterial entry site and hence for proper signaling CC upon cognate peptidoglycan detection (PubMed:31649195, PubMed:34293401, CC PubMed:35066577). Palmitoylation promotes localization to the cell CC membrane (PubMed:34293401). Palmitoylation protects from SQSTM1/p62- CC dependent autophagic degradation (PubMed:35066577). CC {ECO:0000269|PubMed:31649195, ECO:0000269|PubMed:34293401, CC ECO:0000269|PubMed:35066577}. CC -!- PTM: Polyubiquitinated by TRIM27, leading to proteasome-mediated CC degradation (PubMed:22829933). Polyubiquitinated and degraded following CC muramyl dipeptide (MDP) stimulation, conferring MDP tolerance and CC preventing septic shock (PubMed:23019338). CC {ECO:0000269|PubMed:22829933, ECO:0000269|PubMed:23019338}. CC -!- PTM: Degraded via selective autophagy following interaction with IRGM CC (PubMed:35066577, PubMed:36221902). IRGM promotes NOD2-RIPK2 RIPosome CC recruitment to autophagosome membranes, promoting their SQSTM1/p62- CC dependent autophagic degradation (PubMed:36221902). CC {ECO:0000269|PubMed:35066577, ECO:0000269|PubMed:36221902}. CC -!- PTM: O-glycosylated by OGT, O-GlcNAcylation increases protein CC stability. {ECO:0000269|PubMed:26369908}. CC -!- DISEASE: Blau syndrome (BLAUS) [MIM:186580]: An autosomal dominant CC inflammatory disorder characterized by the formation of immune CC granulomas invading the skin, joints and eye. Other organs may be CC involved. Clinical manifestations are variable and include early-onset CC granulomatous arthritis, uveitis and skin rash. Blindness, joint CC destruction and visceral involvement have been reported in severe CC cases. {ECO:0000269|PubMed:11528384, ECO:0000269|PubMed:12626759, CC ECO:0000269|PubMed:15459013, ECO:0000269|PubMed:15812565, CC ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:19169908, CC ECO:0000269|PubMed:19359344, ECO:0000269|PubMed:19479837, CC ECO:0000269|PubMed:20199415, ECO:0000269|PubMed:24960071, CC ECO:0000269|PubMed:25093298, ECO:0000269|PubMed:25692065, CC ECO:0000269|PubMed:25724124, ECO:0000269|PubMed:27812135, CC ECO:0000269|PubMed:34251956}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Inflammatory bowel disease 1 (IBD1) [MIM:266600]: A chronic, CC relapsing inflammation of the gastrointestinal tract with a complex CC etiology. It is subdivided into Crohn disease and ulcerative colitis CC phenotypes. Crohn disease may affect any part of the gastrointestinal CC tract from the mouth to the anus, but most frequently it involves the CC terminal ileum and colon. Bowel inflammation is transmural and CC discontinuous; it may contain granulomas or be associated with CC intestinal or perianal fistulas. In contrast, in ulcerative colitis, CC the inflammation is continuous and limited to rectal and colonic CC mucosal layers; fistulas and granulomas are not observed. Both diseases CC include extraintestinal inflammation of the skin, eyes, or joints. CC {ECO:0000269|PubMed:11385576, ECO:0000269|PubMed:11385577, CC ECO:0000269|PubMed:12514169, ECO:0000269|PubMed:12626759, CC ECO:0000269|PubMed:15024686, ECO:0000269|PubMed:15198989, CC ECO:0000269|PubMed:15998797, ECO:0000269|PubMed:16485124, CC ECO:0000269|PubMed:24790089, ECO:0000269|PubMed:24960071, CC ECO:0000269|PubMed:27812135}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- DISEASE: Yao syndrome (YAOS) [MIM:617321]: An autoinflammatory disease CC characterized by periodic fever, dermatitis, polyarthritis, leg CC swelling, and gastrointestinal and sicca-like symptoms. YAOS is a CC complex disease with multifactorial inheritance. CC {ECO:0000269|PubMed:21914217, ECO:0000269|PubMed:26070941}. CC Note=Disease susceptibility is associated with variants affecting the CC gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 1]: Most abundant isoform. CC {ECO:0000269|PubMed:11087742}. CC -!- SIMILARITY: Belongs to the NOD1-NOD2 family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=INFEVERS; Note=Repertory of FMF and hereditary CC autoinflammatory disorders mutations; CC URL="https://infevers.umai-montpellier.fr/web/search.php?n=6"; 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; AF178930; AAG33677.1; -; mRNA. DR EMBL; AF385089; AAK70867.1; -; Genomic_DNA. DR EMBL; AF385090; AAK70868.1; -; Genomic_DNA. DR EMBL; AJ303140; CAC42117.1; -; Genomic_DNA. DR EMBL; HQ204571; ADN95581.1; -; mRNA. DR CCDS; CCDS10746.1; -. [Q9HC29-1] DR CCDS; CCDS86525.1; -. [Q9HC29-2] DR RefSeq; NP_001280486.1; NM_001293557.1. [Q9HC29-2] DR RefSeq; NP_071445.1; NM_022162.2. [Q9HC29-1] DR RefSeq; XP_005256141.1; XM_005256084.3. DR AlphaFoldDB; Q9HC29; -. DR SMR; Q9HC29; -. DR BioGRID; 122077; 99. DR DIP; DIP-41998N; -. DR IntAct; Q9HC29; 51. DR MINT; Q9HC29; -. DR STRING; 9606.ENSP00000300589; -. DR BindingDB; Q9HC29; -. DR ChEMBL; CHEMBL1293266; -. DR DrugBank; DB13615; Mifamurtide. DR DrugCentral; Q9HC29; -. DR GuidetoPHARMACOLOGY; 1763; -. DR GlyGen; Q9HC29; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q9HC29; -. DR PhosphoSitePlus; Q9HC29; -. DR SwissPalm; Q9HC29; -. DR BioMuta; NOD2; -. DR DMDM; 20137973; -. DR EPD; Q9HC29; -. DR jPOST; Q9HC29; -. DR MassIVE; Q9HC29; -. DR PaxDb; 9606-ENSP00000300589; -. DR PeptideAtlas; Q9HC29; -. DR Antibodypedia; 28302; 555 antibodies from 37 providers. DR DNASU; 64127; -. DR Ensembl; ENST00000300589.6; ENSP00000300589.2; ENSG00000167207.15. [Q9HC29-1] DR Ensembl; ENST00000647318.2; ENSP00000495993.1; ENSG00000167207.15. [Q9HC29-2] DR GeneID; 64127; -. DR KEGG; hsa:64127; -. DR MANE-Select; ENST00000647318.2; ENSP00000495993.1; NM_001370466.1; NP_001357395.1. [Q9HC29-2] DR UCSC; uc002egm.2; human. [Q9HC29-1] DR AGR; HGNC:5331; -. DR CTD; 64127; -. DR DisGeNET; 64127; -. DR GeneCards; NOD2; -. DR HGNC; HGNC:5331; NOD2. DR HPA; ENSG00000167207; Tissue enhanced (bone marrow, esophagus, skin, vagina). DR MalaCards; NOD2; -. DR MIM; 186580; phenotype. DR MIM; 266600; phenotype. DR MIM; 605956; gene. DR MIM; 617321; phenotype. DR neXtProt; NX_Q9HC29; -. DR OpenTargets; ENSG00000167207; -. DR Orphanet; 90340; Blau syndrome. DR Orphanet; 206; NON RARE IN EUROPE: Crohn disease. DR Orphanet; 771; NON RARE IN EUROPE: Ulcerative colitis. DR PharmGKB; PA26074; -. DR VEuPathDB; HostDB:ENSG00000167207; -. DR eggNOG; KOG4308; Eukaryota. DR GeneTree; ENSGT00940000160934; -. DR HOGENOM; CLU_011291_0_0_1; -. DR InParanoid; Q9HC29; -. DR OMA; HCCWPDA; -. DR OrthoDB; 3087860at2759; -. DR PhylomeDB; Q9HC29; -. DR TreeFam; TF352118; -. DR PathwayCommons; Q9HC29; -. DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway. DR Reactome; R-HSA-445989; TAK1-dependent IKK and NF-kappa-B activation. DR Reactome; R-HSA-450302; activated TAK1 mediates p38 MAPK activation. DR Reactome; R-HSA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1. DR Reactome; R-HSA-5689896; Ovarian tumor domain proteases. DR Reactome; R-HSA-9020702; Interleukin-1 signaling. DR Reactome; R-HSA-9705671; SARS-CoV-2 activates/modulates innate and adaptive immune responses. DR SignaLink; Q9HC29; -. DR SIGNOR; Q9HC29; -. DR BioGRID-ORCS; 64127; 17 hits in 1160 CRISPR screens. DR ChiTaRS; NOD2; human. DR GeneWiki; NOD2; -. DR GenomeRNAi; 64127; -. DR Pharos; Q9HC29; Tclin. DR PRO; PR:Q9HC29; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; Q9HC29; Protein. DR Bgee; ENSG00000167207; Expressed in monocyte and 115 other cell types or tissues. DR ExpressionAtlas; Q9HC29; baseline and differential. DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005856; C:cytoskeleton; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0019897; C:extrinsic component of plasma membrane; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell. DR GO; GO:0045335; C:phagocytic vesicle; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB. DR GO; GO:0031982; C:vesicle; IDA:UniProtKB. DR GO; GO:0003779; F:actin binding; IDA:UniProtKB. DR GO; GO:0043531; F:ADP binding; ISS:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0050700; F:CARD domain binding; IPI:UniProtKB. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0030544; F:Hsp70 protein binding; IPI:UniProtKB. DR GO; GO:0051879; F:Hsp90 protein binding; IDA:UniProtKB. DR GO; GO:0032500; F:muramyl dipeptide binding; IDA:UniProtKB. DR GO; GO:0038187; F:pattern recognition receptor activity; IDA:UniProtKB. DR GO; GO:0042834; F:peptidoglycan binding; IDA:HGNC-UCL. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; IPI:UniProtKB. DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB. DR GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW. DR GO; GO:0140367; P:antibacterial innate immune response; IDA:UniProt. DR GO; GO:0002815; P:biosynthetic process of antibacterial peptides active against Gram-positive bacteria; IEA:Ensembl. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IMP:UniProtKB. DR GO; GO:0071225; P:cellular response to muramyl dipeptide; IDA:UniProtKB. DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl. DR GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl. DR GO; GO:0006952; P:defense response; TAS:HGNC-UCL. DR GO; GO:0042742; P:defense response to bacterium; IDA:UniProtKB. DR GO; GO:0016045; P:detection of bacterium; IDA:HGNC-UCL. DR GO; GO:0009595; P:detection of biotic stimulus; TAS:HGNC-UCL. DR GO; GO:0032498; P:detection of muramyl dipeptide; IDA:MGI. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl. DR GO; GO:0048874; P:host-mediated regulation of intestinal microbiota composition; ISS:UniProtKB. DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB. DR GO; GO:0002227; P:innate immune response in mucosa; IEA:Ensembl. DR GO; GO:0036335; P:intestinal stem cell homeostasis; ISS:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IDA:HGNC-UCL. DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl. DR GO; GO:0030277; P:maintenance of gastrointestinal epithelium; IMP:UniProtKB. DR GO; GO:0002862; P:negative regulation of inflammatory response to antigenic stimulus; IEA:Ensembl. DR GO; GO:0032695; P:negative regulation of interleukin-12 production; IEA:Ensembl. DR GO; GO:0032701; P:negative regulation of interleukin-18 production; IEA:Ensembl. DR GO; GO:0032703; P:negative regulation of interleukin-2 production; IEA:Ensembl. DR GO; GO:2000110; P:negative regulation of macrophage apoptotic process; ISS:BHF-UCL. DR GO; GO:0010936; P:negative regulation of macrophage cytokine production; IEA:Ensembl. DR GO; GO:0002710; P:negative regulation of T cell mediated immunity; IEA:Ensembl. DR GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; IEA:Ensembl. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl. DR GO; GO:0032689; P:negative regulation of type II interferon production; IEA:Ensembl. DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IDA:UniProtKB. DR GO; GO:0002221; P:pattern recognition receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0006909; P:phagocytosis; IEA:Ensembl. DR GO; GO:0050871; P:positive regulation of B cell activation; IDA:BHF-UCL. DR GO; GO:0006965; P:positive regulation of biosynthetic process of antibacterial peptides active against Gram-positive bacteria; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:UniProtKB. DR GO; GO:0002720; P:positive regulation of cytokine production involved in immune response; IMP:UniProtKB. DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IDA:CACAO. DR GO; GO:0002606; P:positive regulation of dendritic cell antigen processing and presentation; ISS:BHF-UCL. DR GO; GO:0002732; P:positive regulation of dendritic cell cytokine production; IEA:Ensembl. DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISS:BHF-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:BHF-UCL. DR GO; GO:0046645; P:positive regulation of gamma-delta T cell activation; ISS:BHF-UCL. DR GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:HGNC-UCL. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; ISS:BHF-UCL. DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl. DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IMP:UniProtKB. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IMP:UniProtKB. DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:MGI. DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl. DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:BHF-UCL. DR GO; GO:1901526; P:positive regulation of mitophagy; ISS:UniProtKB. DR GO; GO:0071639; P:positive regulation of monocyte chemotactic protein-1 production; IEA:Ensembl. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISS:BHF-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:0045747; P:positive regulation of Notch signaling pathway; ISS:BHF-UCL. DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IEA:Ensembl. DR GO; GO:0050766; P:positive regulation of phagocytosis; IEA:Ensembl. DR GO; GO:1902523; P:positive regulation of protein K63-linked ubiquitination; IMP:UniProtKB. DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; IDA:MGI. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:MGI. DR GO; GO:0002830; P:positive regulation of type 2 immune response; IMP:BHF-UCL. DR GO; GO:1904417; P:positive regulation of xenophagy; IEA:Ensembl. DR GO; GO:0032098; P:regulation of appetite; ISS:UniProtKB. DR GO; GO:0050727; P:regulation of inflammatory response; IC:BHF-UCL. DR GO; GO:0090022; P:regulation of neutrophil chemotaxis; IEA:Ensembl. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IEA:Ensembl. DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl. DR GO; GO:0032495; P:response to muramyl dipeptide; IDA:UniProtKB. DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl. DR GO; GO:0001659; P:temperature homeostasis; ISS:UniProtKB. DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; IEA:Ensembl. DR GO; GO:0098792; P:xenophagy; IEA:Ensembl. DR CDD; cd08788; CARD_NOD2_2_CARD15; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 2. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 1. DR InterPro; IPR001315; CARD. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR007111; NACHT_NTPase. DR InterPro; IPR041267; NLRP_HD2. DR InterPro; IPR041075; NOD2_WH. DR InterPro; IPR027417; P-loop_NTPase. DR PANTHER; PTHR24106; NACHT, LRR AND CARD DOMAINS-CONTAINING; 1. DR PANTHER; PTHR24106:SF64; NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN-CONTAINING PROTEIN 2; 1. DR Pfam; PF00619; CARD; 1. DR Pfam; PF13516; LRR_6; 3. DR Pfam; PF05729; NACHT; 1. DR Pfam; PF17776; NLRC4_HD2; 1. DR Pfam; PF17779; NOD2_WH; 1. DR SMART; SM00368; LRR_RI; 7. DR SUPFAM; SSF47986; DEATH domain; 2. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR SUPFAM; SSF52047; RNI-like; 1. DR PROSITE; PS50209; CARD; 2. DR PROSITE; PS51450; LRR; 4. DR PROSITE; PS50837; NACHT; 1. DR Genevisible; Q9HC29; HS. PE 1: Evidence at protein level; KW Adaptive immunity; Alternative initiation; ATP-binding; Autophagy; KW Cell membrane; Cytoplasm; Disease variant; Glycoprotein; Immunity; KW Innate immunity; Leucine-rich repeat; Lipoprotein; Membrane; Mitochondrion; KW Nucleotide-binding; Palmitate; Reference proteome; Repeat; Ubl conjugation. FT CHAIN 1..1040 FT /note="Nucleotide-binding oligomerization domain-containing FT protein 2" FT /id="PRO_0000004418" FT DOMAIN 26..122 FT /note="CARD 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046" FT DOMAIN 126..218 FT /note="CARD 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046" FT DOMAIN 293..618 FT /note="NACHT" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136" FT REPEAT 791..812 FT /note="LRR 1" FT REPEAT 816..839 FT /note="LRR 2" FT REPEAT 844..865 FT /note="LRR 3" FT REPEAT 872..884 FT /note="LRR 4" FT REPEAT 900..920 FT /note="LRR 5" FT REPEAT 928..949 FT /note="LRR 6" FT REPEAT 956..976 FT /note="LRR 7" FT REPEAT 984..1005 FT /note="LRR 8" FT REPEAT 1012..1032 FT /note="LRR 9" FT REGION 241..274 FT /note="Required for CARD9 binding" FT /evidence="ECO:0000269|PubMed:24960071" FT MOTIF 63..77 FT /note="ATG16L1-binding motif" FT /evidence="ECO:0000269|PubMed:23376921" FT BINDING 239 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 252 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 253 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 299..306 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136" FT BINDING 302 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 303 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 304 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 305 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 306 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 307 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT BINDING 603 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:G1T469" FT LIPID 395 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:31649195, FT ECO:0000269|PubMed:34293401, ECO:0000269|PubMed:35066577" FT LIPID 1033 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000269|PubMed:31649195, FT ECO:0000269|PubMed:34293401, ECO:0000269|PubMed:35066577" FT VAR_SEQ 1..27 FT /note="Missing (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:11087742, FT ECO:0000303|PubMed:20698950" FT /id="VSP_018689" FT VAR_SEQ 216..224 FT /note="AATCKKYMA -> DERTEAQKG (in isoform 3)" FT /evidence="ECO:0000303|PubMed:20698950" FT /id="VSP_046567" FT VAR_SEQ 225..1040 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:20698950" FT /id="VSP_046568" FT VARIANT 81 FT /note="L -> V (in dbSNP:rs34936594)" FT /id="VAR_036871" FT VARIANT 113 FT /note="D -> N (in IBD1; uncertain significance; FT dbSNP:rs104895468)" FT /evidence="ECO:0000269|PubMed:15024686" FT /id="VAR_073228" FT VARIANT 140 FT /note="A -> T (in IBD1; uncertain significance; FT dbSNP:rs34684955)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012665" FT VARIANT 157 FT /note="W -> R (in IBD1; uncertain significance; FT dbSNP:rs104895420)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012666" FT VARIANT 189 FT /note="T -> M (in dbSNP:rs61755182)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012667" FT VARIANT 235 FT /note="R -> C (in IBD1; uncertain significance; FT dbSNP:rs104895422)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012668" FT VARIANT 248 FT /note="L -> R (in IBD1; uncertain significance; no FT disruption of NOD2-CARD9 interaction; dbSNP:rs104895423)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:24960071" FT /id="VAR_012669" FT VARIANT 268 FT /note="P -> S (in dbSNP:rs2066842)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:16485124, ECO:0000269|PubMed:25724124" FT /id="VAR_012670" FT VARIANT 289 FT /note="N -> S (in dbSNP:rs5743271)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:16485124" FT /id="VAR_012671" FT VARIANT 291 FT /note="D -> N (in IBD1; uncertain significance; FT dbSNP:rs104895424)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012672" FT VARIANT 294 FT /note="T -> S (in IBD1; uncertain significance; FT dbSNP:rs104895425)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012673" FT VARIANT 301 FT /note="A -> V (in IBD1; uncertain significance; FT dbSNP:rs104895426)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012674" FT VARIANT 311 FT /note="R -> W (in IBD1; uncertain significance; FT dbSNP:rs104895427)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:16485124" FT /id="VAR_012675" FT VARIANT 334 FT /note="R -> Q (in BLAUS; somatic mosaicism in 4.9% to 11% FT of peripheral blood cells; hyperactive; constitutive FT NF-kappa-B activation in absence of muramyl dipeptide FT stimulation; abolishes interaction with LDOC1, ANKHD1, FT PPP2R3B, ENTR1 and TRIM41; decreases interaction with RIPK2 FT and PPP1R12C; no effect on interaction with CHMP5; FT dbSNP:rs104895461)" FT /evidence="ECO:0000269|PubMed:11528384, FT ECO:0000269|PubMed:12626759, ECO:0000269|PubMed:19116920, FT ECO:0000269|PubMed:19479837, ECO:0000269|PubMed:25093298, FT ECO:0000269|PubMed:25724124, ECO:0000269|PubMed:27812135" FT /id="VAR_012676" FT VARIANT 334 FT /note="R -> W (in BLAUS; no disruption of NOD2-CARD9 FT interaction; hyperactive; constitutive NF-kappa-B FT activation in absence of muramyl dipeptide stimulation; FT dbSNP:rs104895462)" FT /evidence="ECO:0000269|PubMed:11528384, FT ECO:0000269|PubMed:12626759, ECO:0000269|PubMed:15459013, FT ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:19479837, FT ECO:0000269|PubMed:20199415, ECO:0000269|PubMed:24960071, FT ECO:0000269|PubMed:25093298" FT /id="VAR_012677" FT VARIANT 348 FT /note="L -> V (in IBD1; uncertain significance; FT dbSNP:rs104895428)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012678" FT VARIANT 352 FT /note="H -> R (in IBD1; uncertain significance; FT dbSNP:rs5743272)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012679" FT VARIANT 357 FT /note="D -> A (in IBD1; uncertain significance; no FT disruption of NOD2-CARD9 interaction; dbSNP:rs104895469)" FT /evidence="ECO:0000269|PubMed:15024686, FT ECO:0000269|PubMed:24960071" FT /id="VAR_073229" FT VARIANT 363 FT /note="I -> F (in IBD1; uncertain significance; no FT disruption of NOD2-CARD9 interaction; dbSNP:rs104895470)" FT /evidence="ECO:0000269|PubMed:15024686, FT ECO:0000269|PubMed:24960071" FT /id="VAR_073230" FT VARIANT 373 FT /note="R -> C (in IBD1; uncertain significance; FT dbSNP:rs145293873)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012680" FT VARIANT 382 FT /note="D -> E (in BLAUS; hyperactive; dbSNP:rs104895476)" FT /evidence="ECO:0000269|PubMed:15459013, FT ECO:0000269|PubMed:19116920" FT /id="VAR_023822" FT VARIANT 383 FT /note="E -> G (in BLAUS; uncertain significance; FT hyperactive; dbSNP:rs104895493)" FT /evidence="ECO:0000269|PubMed:19116920, FT ECO:0000269|PubMed:25093298" FT /id="VAR_073231" FT VARIANT 383 FT /note="E -> K (in BLAUS; hyperactive; dbSNP:rs104895477)" FT /evidence="ECO:0000269|PubMed:15812565, FT ECO:0000269|PubMed:19479837, ECO:0000269|PubMed:25093298" FT /id="VAR_023823" FT VARIANT 391 FT /note="R -> C (in dbSNP:rs104895481)" FT /evidence="ECO:0000269|PubMed:16485124" FT /id="VAR_073232" FT VARIANT 414 FT /note="N -> S (in IBD1; uncertain significance; FT dbSNP:rs104895429)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012681" FT VARIANT 431 FT /note="S -> L (in IBD1; uncertain significance; no FT disruption of NOD2-CARD9 interaction; dbSNP:rs104895431)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:24960071" FT /id="VAR_012682" FT VARIANT 432 FT /note="A -> V (in IBD1; uncertain significance; FT dbSNP:rs2076754)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012683" FT VARIANT 441 FT /note="E -> K (in IBD1; uncertain significance; no FT disruption of NOD2-CARD9 interaction; dbSNP:rs104895432)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:24960071" FT /id="VAR_012684" FT VARIANT 463 FT /note="P -> A (no disruption of NOD2-CARD9 interaction; FT dbSNP:rs104895482)" FT /evidence="ECO:0000269|PubMed:16485124, FT ECO:0000269|PubMed:24960071" FT /id="VAR_073233" FT VARIANT 464 FT /note="G -> W (hyperactive; dbSNP:rs104895492)" FT /evidence="ECO:0000269|PubMed:25093298" FT /id="VAR_073234" FT VARIANT 469 FT /note="L -> F (in BLAUS; hyperactive; constitutive FT NF-kappa-B activation in absence of muramyl dipeptide FT stimulation; dbSNP:rs104895460)" FT /evidence="ECO:0000269|PubMed:11528384, FT ECO:0000269|PubMed:12626759, ECO:0000269|PubMed:25093298" FT /id="VAR_012685" FT VARIANT 471 FT /note="R -> C (does not affect activity; dbSNP:rs1078327)" FT /evidence="ECO:0000269|PubMed:25093298" FT /id="VAR_036872" FT VARIANT 481 FT /note="G -> D (in BLAUS; atypical form with cardiac FT infiltration; sporadic case; uncertain significance; FT hyperactive; dbSNP:rs104895494)" FT /evidence="ECO:0000269|PubMed:19359344, FT ECO:0000269|PubMed:25093298" FT /id="VAR_073235" FT VARIANT 490 FT /note="W -> L (in BLAUS; uncertain significance; FT hyperactive; dbSNP:rs104895480)" FT /evidence="ECO:0000269|PubMed:19479837, FT ECO:0000269|PubMed:25093298" FT /id="VAR_073236" FT VARIANT 495 FT /note="C -> Y (in BLAUS; uncertain significance; FT hyperactive; dbSNP:rs104895478)" FT /evidence="ECO:0000269|PubMed:19116920, FT ECO:0000269|PubMed:19479837, ECO:0000269|PubMed:25093298" FT /id="VAR_073237" FT VARIANT 496 FT /note="H -> L (in BLAUS; hyperactive; dbSNP:rs104895472)" FT /evidence="ECO:0000269|PubMed:15459013, FT ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:25093298" FT /id="VAR_023824" FT VARIANT 498 FT /note="E -> D (in BLAUS)" FT /evidence="ECO:0000269|PubMed:34251956" FT /id="VAR_088136" FT VARIANT 507 FT /note="P -> S (in BLAUS)" FT /evidence="ECO:0000269|PubMed:25692065" FT /id="VAR_073180" FT VARIANT 513 FT /note="M -> T (in BLAUS; hyperactive; dbSNP:rs104895473)" FT /evidence="ECO:0000269|PubMed:15459013, FT ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:25093298" FT /id="VAR_073238" FT VARIANT 550 FT /note="L -> V (in IBD1; uncertain significance; no FT disruption of NOD2-CARD9 interaction; dbSNP:rs104895471)" FT /evidence="ECO:0000269|PubMed:15024686, FT ECO:0000269|PubMed:24960071" FT /id="VAR_073239" FT VARIANT 587 FT /note="R -> C (in BLAUS; uncertain significance; not FT hyperactive; dbSNP:rs104895479)" FT /evidence="ECO:0000269|PubMed:19479837, FT ECO:0000269|PubMed:25093298" FT /id="VAR_073240" FT VARIANT 605 FT /note="T -> N (in BLAUS; hyperactive)" FT /evidence="ECO:0000269|PubMed:19169908, FT ECO:0000269|PubMed:25093298" FT /id="VAR_065228" FT VARIANT 605 FT /note="T -> P (in BLAUS; hyperactive; dbSNP:rs104895474)" FT /evidence="ECO:0000269|PubMed:15459013, FT ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:25093298" FT /id="VAR_073241" FT VARIANT 612 FT /note="A -> T (in BLAUS and IBD1; uncertain significance; FT dbSNP:rs104895438)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:15459013" FT /id="VAR_012686" FT VARIANT 612 FT /note="A -> V (in IBD1; uncertain significance; no FT disruption of NOD2-CARD9 interaction; dbSNP:rs104895439)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:24960071" FT /id="VAR_012687" FT VARIANT 670 FT /note="N -> K (in BLAUS; hyperactive; dbSNP:rs104895475)" FT /evidence="ECO:0000269|PubMed:15459013, FT ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:25093298" FT /id="VAR_073242" FT VARIANT 684 FT /note="R -> W (in IBD1; uncertain significance; FT dbSNP:rs5743276)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012688" FT VARIANT 702 FT /note="R -> W (in IBD1 and YAOS; associated with disease FT susceptibility; decreased NF-kappa-B activation in response FT to muramyl dipeptide stimulation; no disruption of FT NOD2-CARD9 interaction; decreases half-life of protein; FT abolishes interaction with ANKHD1, ENTR1 and TRIM41; FT increases interaction with RIPK2 and PPP2R3B; decreases FT interaction with LDOC1 and PPP1R12C; no effect on FT interaction with CHMP5; decreased NF-kappa-B activation in FT response to muramyl dipeptide stimulation; FT dbSNP:rs2066844)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:12514169, ECO:0000269|PubMed:12626759, FT ECO:0000269|PubMed:15198989, ECO:0000269|PubMed:16485124, FT ECO:0000269|PubMed:21914217, ECO:0000269|PubMed:24790089, FT ECO:0000269|PubMed:24960071, ECO:0000269|PubMed:27812135" FT /id="VAR_012689" FT VARIANT 703 FT /note="R -> C (in IBD1; uncertain significance; FT dbSNP:rs5743277)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:16485124" FT /id="VAR_012690" FT VARIANT 713 FT /note="R -> C (in IBD1; uncertain significance; FT dbSNP:rs104895440)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012691" FT VARIANT 713 FT /note="R -> H (in IBD1; uncertain significance; FT dbSNP:rs104895483)" FT /evidence="ECO:0000269|PubMed:16485124" FT /id="VAR_073243" FT VARIANT 725 FT /note="A -> G (in IBD1; uncertain significance; FT dbSNP:rs5743278)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012692" FT VARIANT 755 FT /note="A -> V (in IBD1; uncertain significance; FT dbSNP:rs61747625)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:16485124" FT /id="VAR_012693" FT VARIANT 758 FT /note="A -> V (in IBD1; uncertain significance; FT dbSNP:rs104895442)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012694" FT VARIANT 760 FT /note="R -> C (in IBD1; uncertain significance; FT dbSNP:rs3813758)" FT /evidence="ECO:0000269|PubMed:16485124" FT /id="VAR_073244" FT VARIANT 778 FT /note="E -> K (in IBD1; uncertain significance; FT dbSNP:rs104895443)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012695" FT VARIANT 790 FT /note="R -> Q (in dbSNP:rs5743279)" FT /id="VAR_024402" FT VARIANT 790 FT /note="R -> W (in IBD1; uncertain significance; FT dbSNP:rs62029861)" FT /evidence="ECO:0000269|PubMed:16485124" FT /id="VAR_073245" FT VARIANT 791 FT /note="R -> W (in dbSNP:rs104895484)" FT /evidence="ECO:0000269|PubMed:16485124" FT /id="VAR_073246" FT VARIANT 793 FT /note="V -> M (in IBD1; uncertain significance; FT dbSNP:rs104895444)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012696" FT VARIANT 825 FT /note="N -> K (in dbSNP:rs104895485)" FT /evidence="ECO:0000269|PubMed:16485124" FT /id="VAR_073247" FT VARIANT 843 FT /note="E -> K (in IBD1; uncertain significance; FT dbSNP:rs104895445)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012697" FT VARIANT 849 FT /note="A -> V (in dbSNP:rs104895486)" FT /evidence="ECO:0000269|PubMed:16485124" FT /id="VAR_073248" FT VARIANT 852 FT /note="N -> S (in IBD1; uncertain significance; FT dbSNP:rs104895467)" FT /evidence="ECO:0000269|PubMed:15024686" FT /id="VAR_073249" FT VARIANT 853 FT /note="N -> S (in IBD1; uncertain significance; FT dbSNP:rs104895446)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012698" FT VARIANT 863 FT /note="M -> V (in IBD1; decreased NF-kappa-B activation in FT response to muramyl dipeptide stimulation; FT dbSNP:rs104895447)" FT /evidence="ECO:0000269|PubMed:11385576, FT ECO:0000269|PubMed:12514169, ECO:0000269|PubMed:12626759" FT /id="VAR_012699" FT VARIANT 885 FT /note="A -> T (in IBD1; uncertain significance)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012700" FT VARIANT 908 FT /note="G -> R (in IBD1 and YAOS; associated with disease FT susceptibility; decreased NF-kappa-B activation in response FT to muramyl dipeptide stimulation; decreases half-life of FT protein; abolishes interaction with ANKHD1, ENTR1 and FT TRIM41; decreases interaction with RIPK2 and PPP1R12C; no FT effect on interaction with CHMP5, LDOC1 and PPP2R3B; FT dbSNP:rs2066845)" FT /evidence="ECO:0000269|PubMed:11087742, FT ECO:0000269|PubMed:11385576, ECO:0000269|PubMed:12514169, FT ECO:0000269|PubMed:15198989, ECO:0000269|PubMed:16485124, FT ECO:0000269|PubMed:24790089, ECO:0000269|PubMed:26070941, FT ECO:0000269|PubMed:27812135" FT /id="VAR_012701" FT VARIANT 918 FT /note="A -> D (in dbSNP:rs104895452)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012702" FT VARIANT 924 FT /note="G -> D (in IBD1; uncertain significance; FT dbSNP:rs104895453)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012703" FT VARIANT 955 FT /note="V -> I (in dbSNP:rs5743291)" FT /evidence="ECO:0000269|PubMed:11385576" FT /id="VAR_012704" FT VARIANT 1007..1040 FT /note="LERNDTILEVWLRGNTFSLEEVDKLGCRDTRLLL -> P (in IBD1; FT abolished NF-kappa-B activation in response to muramyl FT dipeptide stimulation; decreased localization to the cell FT membrane)" FT /evidence="ECO:0000269|PubMed:11385577, FT ECO:0000269|PubMed:12514169, ECO:0000269|PubMed:12626759, FT ECO:0000269|PubMed:15198989, ECO:0000269|PubMed:15998797" FT /id="VAR_088137" FT MUTAGEN 31 FT /note="Q->H: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation. Decreased interaction with FT RIPK2." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 69 FT /note="E->K: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 91 FT /note="T->I: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 104 FT /note="I->R: Abolished binding to ubiquitin; when FT associated with R-200." FT /evidence="ECO:0000269|PubMed:23300079" FT MUTAGEN 106 FT /note="A->V: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation. Decreased interaction with FT RIPK2." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 145 FT /note="L->P: Dominant-negative mutant. Abolished NF-kappa-B FT activation in response to muramyl dipeptide stimulation. FT Decreased interaction with RIPK2." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 152 FT /note="M->L: Does not affect NF-kappa-B activation in FT response to muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 177 FT /note="P->S: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 180 FT /note="R->K: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 200 FT /note="L->R: Abolished binding to ubiquitin; when FT associated with R-104." FT /evidence="ECO:0000269|PubMed:23300079" FT MUTAGEN 232 FT /note="A->P: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 295 FT /note="V->E: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 305 FT /note="K->R: No activation." FT /evidence="ECO:0000269|PubMed:11087742" FT MUTAGEN 327 FT /note="F->Y: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 333 FT /note="C->Y: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 334 FT /note="R->A: Increased NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 344 FT /note="S->T: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 379 FT /note="D->A: No disruption in NOD2-CARD9 interaction. FT Decreased NF-kappa-B activation in response to muramyl FT dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951, FT ECO:0000269|PubMed:24960071" FT MUTAGEN 395 FT /note="C->S: Abolished palmitoylation and localization to FT the cell membrane; when associated with S-1033." FT /evidence="ECO:0000269|PubMed:31649195, FT ECO:0000269|PubMed:34293401, ECO:0000269|PubMed:35066577" FT MUTAGEN 396 FT /note="S->Y: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 401 FT /note="T->I,S: Abolished NF-kappa-B activation in response FT to muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 408 FT /note="F->L: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 426 FT /note="R->A: Does not affect NF-kappa-B activation in FT response to muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 429 FT /note="A->T: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 481 FT /note="G->A: Increased NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 492 FT /note="V->E: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 600 FT /note="E->A: Increased NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 603 FT /note="H->A: Does not affect NF-kappa-B activation in FT response to muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 626 FT /note="L->F: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 637 FT /note="N->I: Constitutive NF-kappa-B activation; when FT associated with V-725." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 639 FT /note="P->S: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 655 FT /note="K->E: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 668 FT /note="P->H: Constitutive NF-kappa-B activation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 670 FT /note="N->A: Increased NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 673 FT /note="I->F: Constitutive NF-kappa-B activation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 680 FT /note="G->R: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 680 FT /note="Missing: Constitutive NF-kappa-B activation; when FT associated with Y-710." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 690 FT /note="L->P: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 691 FT /note="A->T: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 710 FT /note="C->Y: Constitutive NF-kappa-B activation; when FT associated with R-680." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 714 FT /note="S->N: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 719 FT /note="F->I: Constitutive NF-kappa-B activation; when FT associated with R-731." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 725 FT /note="A->V: Constitutive NF-kappa-B activation; when FT associated with I-637." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 731 FT /note="K->R: Constitutive NF-kappa-B activation; when FT associated with I-719." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 734 FT /note="H->L: Abolished NF-kappa-B activation in response to FT muramyl dipeptide stimulation." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 761 FT /note="G->H: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 762 FT /note="L->M: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 793 FT /note="V->M: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 799 FT /note="Y->A: Does not affect response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 805 FT /note="I->N: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 812 FT /note="P->T: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 823 FT /note="R->A: Slightly decreased response to muramyl FT dipeptide (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 824 FT /note="D->A: Does not affect response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 824 FT /note="D->N: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 851 FT /note="F->A: Decreased response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 852 FT /note="N->A: Does not affect response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 860 FT /note="A->G: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 876 FT /note="L->I: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 877 FT /note="R->A: Strongly decreased binding to muramyl FT dipeptide (MDP)." FT /evidence="ECO:0000269|PubMed:27283905, FT ECO:0000269|PubMed:27748583" FT MUTAGEN 889 FT /note="Q->P: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 891 FT /note="L->M: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 892 FT /note="A->V: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 904 FT /note="L->M: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 905 FT /note="G->A: Decreased response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 907 FT /note="W->A: Decreased response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 913 FT /note="D->V: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 920 FT /note="A->T: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 931 FT /note="W->A: Strongly decreased binding to muramyl FT dipeptide (MDP)." FT /evidence="ECO:0000269|PubMed:27283905, FT ECO:0000269|PubMed:27748583" FT MUTAGEN 933 FT /note="S->A: Decreased binding to muramyl dipeptide (MDP)." FT /evidence="ECO:0000269|PubMed:27283905, FT ECO:0000269|PubMed:27748583" FT MUTAGEN 935 FT /note="V->A: Slightly decreased response to muramyl FT dipeptide (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 936 FT /note="G->A: Does not affect response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 944 FT /note="A->V: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 947 FT /note="L->M: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 949 FT /note="L->M: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 956 FT /note="M->T: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 961 FT /note="C->A: Does not affect response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 964 FT /note="E->A: Does not affect response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 968 FT /note="Q->H: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 978 FT /note="G->E: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 984 FT /note="S->T: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 986 FT /note="K->I: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 992 FT /note="N->A: Does not affect response to muramyl dipeptide FT (MDP)." FT /evidence="ECO:0000269|PubMed:27283905" FT MUTAGEN 1002 FT /note="A->S: Abolished pattern recognition receptor FT activity." FT /evidence="ECO:0000269|PubMed:15044951" FT MUTAGEN 1017..1019 FT /note="WLR->GGG: Abolished localization to the cell FT membrane." FT /evidence="ECO:0000269|PubMed:15998797" FT MUTAGEN 1017 FT /note="W->G: Decreased ability to promote NF-kappa-B FT activation." FT /evidence="ECO:0000269|PubMed:15998797" FT MUTAGEN 1018 FT /note="L->G: Decreased ability to promote NF-kappa-B FT activation." FT /evidence="ECO:0000269|PubMed:15998797" FT MUTAGEN 1019 FT /note="R->G: Does not affect ability to promote NF-kappa-B FT activation." FT /evidence="ECO:0000269|PubMed:15998797" FT MUTAGEN 1033 FT /note="C->S: Abolished palmitoylation and localization to FT the cell membrane; when associated with S-395." FT /evidence="ECO:0000269|PubMed:31649195, FT ECO:0000269|PubMed:34293401, ECO:0000269|PubMed:35066577" FT MUTAGEN 1039..1040 FT /note="LL->GG: Abolished localization to the cell FT membrane." FT /evidence="ECO:0000269|PubMed:15998797" FT VARIANT Q9HC29-2:444 FT /note="R -> C (increased palmitoylation and protein FT stability, leading to constitutive NF-kappa-B activation)" FT /evidence="ECO:0000269|PubMed:35066577" FT /id="VAR_088138" SQ SEQUENCE 1040 AA; 115283 MW; 0037592D96D7DDFF CRC64; MGEEGGSASH DEEERASVLL GHSPGCEMCS QEAFQAQRSQ LVELLVSGSL EGFESVLDWL LSWEVLSWED YEGFHLLGQP LSHLARRLLD TVWNKGTWAC QKLIAAAQEA QADSQSPKLH GCWDPHSLHP ARDLQSHRPA IVRRLHSHVE NMLDLAWERG FVSQYECDEI RLPIFTPSQR ARRLLDLATV KANGLAAFLL QHVQELPVPL ALPLEAATCK KYMAKLRTTV SAQSRFLSTY DGAETLCLED IYTENVLEVW ADVGMAGPPQ KSPATLGLEE LFSTPGHLND DADTVLVVGE AGSGKSTLLQ RLHLLWAAGQ DFQEFLFVFP FSCRQLQCMA KPLSVRTLLF EHCCWPDVGQ EDIFQLLLDH PDRVLLTFDG FDEFKFRFTD RERHCSPTDP TSVQTLLFNL LQGNLLKNAR KVVTSRPAAV SAFLRKYIRT EFNLKGFSEQ GIELYLRKRH HEPGVADRLI RLLQETSALH GLCHLPVFSW MVSKCHQELL LQEGGSPKTT TDMYLLILQH FLLHATPPDS ASQGLGPSLL RGRLPTLLHL GRLALWGLGM CCYVFSAQQL QAAQVSPDDI SLGFLVRAKG VVPGSTAPLE FLHITFQCFF AAFYLALSAD VPPALLRHLF NCGRPGNSPM ARLLPTMCIQ ASEGKDSSVA ALLQKAEPHN LQITAAFLAG LLSREHWGLL AECQTSEKAL LRRQACARWC LARSLRKHFH SIPPAAPGEA KSVHAMPGFI WLIRSLYEMQ EERLARKAAR GLNVGHLKLT FCSVGPTECA ALAFVLQHLR RPVALQLDYN SVGDIGVEQL LPCLGVCKAL YLRDNNISDR GICKLIECAL HCEQLQKLAL FNNKLTDGCA HSMAKLLACR QNFLALRLGN NYITAAGAQV LAEGLRGNTS LQFLGFWGNR VGDEGAQALA EALGDHQSLR WLSLVGNNIG SVGAQALALM LAKNVMLEEL CLEENHLQDE GVCSLAEGLK KNSSLKILKL SNNCITYLGA EALLQALERN DTILEVWLRG NTFSLEEVDK LGCRDTRLLL //