NOD2_HUMAN
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 03-AUG-2022, entry version 211.
DE RecName: Full=Nucleotide-binding oligomerization domain-containing protein 2;
DE AltName: Full=Caspase recruitment domain-containing protein 15;
DE AltName: Full=Inflammatory bowel disease protein 1;
GN Name=NOD2; Synonyms=CARD15, IBD1;
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, INTERACTION WITH RIPK2, AND TISSUE 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).
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 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 [5]
RP INTERACTION WITH ERBBI2P, AND SUBCELLULAR LOCATION.
RX PubMed=16203728; DOI=10.1074/jbc.m508538200;
RA McDonald C., Chen F.F., Ollendorff V., Ogura Y., Marchetto S., 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 [6]
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 [7]
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 [8]
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 [9]
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 [10]
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 [11]
RP TISSUE SPECIFICITY, 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 [12]
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 [13]
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 [14]
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 [15]
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 [16]
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 [17]
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 [18]
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 [19]
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 [20]
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 [21]
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 [22]
RP PALMITOYLATION, 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 [23]
RP FUNCTION.
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 [24]
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 [25]
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 [26]
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 [27]
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 [28]
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 [29]
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 [30]
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 [31]
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 [32]
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 [33]
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 [34]
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 [35]
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 [36]
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 [37]
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).
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:12527755). Upon stimulation
CC by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan,
CC binds the proximal adapter receptor-interacting RIPK2, which recruits
CC ubiquitin ligases as XIAP, BIRC2, BIRC3, INAVA and the LUBAC complex,
CC triggering activation of MAP kinases and activation of NF-kappa-B
CC signaling (PubMed:11087742, PubMed:21887730). This in turn leads to the
CC transcriptional activation of hundreds of genes involved in immune
CC response. Required for MDP-induced NLRP1-dependent CASP1 activation and
CC IL1B release in macrophages (PubMed:18511561). Component of an
CC autophagy-mediated antibacterial pathway together with ATG16L1
CC (PubMed:20637199). Also plays a role in sensing single-stranded RNA
CC (ssRNA) from viruses. Interacts with mitochondrial antiviral
CC signaling/MAVS, leading to activation of interferon regulatory factor-
CC 3/IRF3 and expression of type I interferon (PubMed:19701189). Besides
CC recognizing pathogens, participates in surveillance of cellular
CC homeostasis through sensing and binding to the cytosolic metabolite
CC sphingosine-1-phosphate and then initating inflammation process
CC (PubMed:33942347). {ECO:0000269|PubMed:18511561,
CC ECO:0000269|PubMed:19701189, ECO:0000269|PubMed:20637199,
CC ECO:0000269|PubMed:23806334, ECO:0000269|PubMed:28436939,
CC ECO:0000269|PubMed:33942347}.
CC -!- SUBUNIT: Component of a signaling complex consisting of ARHGEF2, NOD2
CC and RIPK2 (PubMed:11087742, PubMed:21887730). Interacts (via CARD
CC domain) with RIPK2 (via CARD domain) (PubMed:19592251, PubMed:21887730,
CC PubMed:27812135). Interacts with ATG16L1 (PubMed:20637199,
CC PubMed:23376921). Interacts (via NACHT domain) with CARD9
CC (PubMed:24960071). 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
CC ERBBI2P; the interaction inhibits activation of NOD2 (PubMed:16203728).
CC Interacts (via CARD domain) with CASP1; this interaction leads to IL1B
CC processing. Also interacts with CASP4. Interacts with NLRP1; this
CC interaction is enhanced in the presence of muramyl dipeptide (MDP) and
CC leads to increased IL1B release (PubMed:18511561). Interacts with
CC MAPKBP1; the interaction is enhanced in the presence of muramyl
CC dipeptide (MDP) (PubMed:22700971). Interacts with INAVA; the
CC interaction takes place upon PRR stimulation (PubMed:28436939).
CC Interacts with ANKHD1, C10ORF67, CHMP5, DOCK7, ENTR1, KRT15, LDOC1,
CC PPP1R12C, PPP2R3B, TRIM41 and VIM (PubMed:27812135). Interacts with
CC NLRP12; this interaction promotes degradation of NOD2 through the
CC ubiquitin-proteasome pathway (PubMed:30559449).
CC {ECO:0000269|PubMed:11087742, ECO:0000269|PubMed:16203728,
CC ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:19592251,
CC ECO:0000269|PubMed:20637199, ECO:0000269|PubMed:21887730,
CC ECO:0000269|PubMed:22700971, ECO:0000269|PubMed:23019338,
CC ECO:0000269|PubMed:23376921, ECO:0000269|PubMed:23711367,
CC ECO:0000269|PubMed:24790089, ECO:0000269|PubMed:24960071,
CC ECO:0000269|PubMed:27812135, ECO:0000269|PubMed:28436939,
CC ECO:0000269|PubMed:30559449}.
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:31649195}.
CC Cytoplasm {ECO:0000269|PubMed:19701189, ECO:0000269|PubMed:24790089,
CC ECO:0000269|PubMed:25093298}. Membrane {ECO:0000269|PubMed:25093298}.
CC Mitochondrion {ECO:0000269|PubMed:19701189}. Basolateral cell membrane
CC {ECO:0000269|PubMed:16203728}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative initiation; Named isoforms=3;
CC Name=1; Synonyms=Nod2;
CC IsoId=Q9HC29-1; Sequence=Displayed;
CC Name=2; Synonyms=Nod2b;
CC IsoId=Q9HC29-2; Sequence=VSP_018689;
CC Name=3; Synonyms=NOD2-C2;
CC IsoId=Q9HC29-3; Sequence=VSP_018689, VSP_046567, VSP_046568;
CC -!- TISSUE SPECIFICITY: Mainly expressed in monocytes (PubMed:11087742).
CC Expressed also in intestinal mucosa, mainly in Paneth cells and, at
CC lower extent, in the glandular epithelium (PubMed:22700971).
CC {ECO:0000269|PubMed:11087742, ECO:0000269|PubMed:22700971}.
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. In the absence of LRRs, the protein
CC becomes a constitutive activator of CASP1 cleavage and proIL1B
CC processing. {ECO:0000269|PubMed:18511561}.
CC -!- PTM: Palmitoylated. Palmitoylation is required for proper recruitment
CC to the bacterial entry site and hence for proper signaling upon cognate
CC peptidoglycan detection. {ECO:0000269|PubMed:31649195}.
CC -!- PTM: Polyubiquitinated following MDP stimulation, leading to
CC proteasome-mediated degradation (PubMed:23019338).
CC {ECO:0000269|PubMed:23019338}.
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:15459013,
CC ECO:0000269|PubMed:15812565, ECO:0000269|PubMed:19116920,
CC ECO:0000269|PubMed:19169908, ECO:0000269|PubMed:19359344,
CC ECO:0000269|PubMed:19479837, ECO:0000269|PubMed:20199415,
CC ECO:0000269|PubMed:24960071, ECO:0000269|PubMed:25093298,
CC ECO:0000269|PubMed:25692065, ECO:0000269|PubMed:25724124,
CC ECO:0000269|PubMed:27812135}. 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:15024686,
CC ECO:0000269|PubMed:16485124, ECO:0000269|PubMed:24790089,
CC ECO:0000269|PubMed:24960071, ECO:0000269|PubMed:27812135}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC 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]: Can activate NF-kappa-B. More abundant.
CC -!- MISCELLANEOUS: [Isoform 2]: Can activate NF-kappa-B. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Can activate NF-kappa-B. {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";
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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; 97.
DR DIP; DIP-41998N; -.
DR IntAct; Q9HC29; 50.
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 BioMuta; NOD2; -.
DR DMDM; 20137973; -.
DR EPD; Q9HC29; -.
DR jPOST; Q9HC29; -.
DR PaxDb; Q9HC29; -.
DR PeptideAtlas; Q9HC29; -.
DR PRIDE; Q9HC29; -.
DR Antibodypedia; 28302; 500 antibodies from 37 providers.
DR DNASU; 64127; -.
DR Ensembl; ENST00000300589.6; ENSP00000300589.2; ENSG00000167207.14. [Q9HC29-1]
DR Ensembl; ENST00000647318.2; ENSP00000495993.1; ENSG00000167207.14. [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 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; FWGNKVG; -.
DR OrthoDB; 651627at2759; -.
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 1082 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 114 other tissues.
DR ExpressionAtlas; Q9HC29; baseline and differential.
DR Genevisible; Q9HC29; HS.
DR GO; GO:0046658; C:anchored component of plasma membrane; IMP:UniProtKB.
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: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: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:HGNC-UCL.
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:0002253; P:activation of immune response; IEA:Ensembl.
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:HGNC-UCL.
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:HGNC-UCL.
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:0007249; P:I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
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: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:0032689; P:negative regulation of interferon-gamma production; 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:0032088; P:negative regulation of NF-kappaB transcription factor activity; 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:0038061; P:NIK/NF-kappaB signaling; 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:0018108; P:peptidyl-tyrosine phosphorylation; IEA:Ensembl.
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: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:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:0045089; P:positive regulation of innate immune response; 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:0043406; P:positive regulation of MAP kinase activity; ISS:BHF-UCL.
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:1901224; P:positive regulation of NIK/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISS:BHF-UCL.
DR GO; GO:0045747; P:positive regulation of Notch signaling pathway; ISS:BHF-UCL.
DR GO; GO:0051353; P:positive regulation of oxidoreductase activity; 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:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISS:BHF-UCL.
DR GO; GO:2000363; P:positive regulation of prostaglandin-E synthase activity; ISS:BHF-UCL.
DR GO; GO:0060585; P:positive regulation of prostaglandin-endoperoxide synthase activity; ISS:BHF-UCL.
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:0050727; P:regulation of inflammatory response; IC:BHF-UCL.
DR GO; GO:0090022; P:regulation of neutrophil chemotaxis; IEA:Ensembl.
DR GO; GO:0043330; P:response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0032495; P:response to muramyl dipeptide; IDA:HGNC-UCL.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; IEA:Ensembl.
DR GO; GO:0098792; P:xenophagy; IEA:Ensembl.
DR Gene3D; 1.10.533.10; -; 2.
DR Gene3D; 3.40.50.300; -; 1.
DR Gene3D; 3.80.10.10; -; 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 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 SUPFAM; SSF47986; SSF47986; 2.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50209; CARD; 2.
DR PROSITE; PS51450; LRR; 4.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW Alternative initiation; ATP-binding; Cell membrane; Cytoplasm;
KW Disease variant; Immunity; Innate immunity; Leucine-rich repeat;
KW Lipoprotein; Membrane; Mitochondrion; Nucleotide-binding; Palmitate;
KW 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 BINDING 299..306
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
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; unknown pathological significance;
FT dbSNP:rs104895468)"
FT /evidence="ECO:0000269|PubMed:15024686"
FT /id="VAR_073228"
FT VARIANT 140
FT /note="A -> T (in IBD1; also found in patients with
FT ulcerative colitis; unknown pathological significance;
FT dbSNP:rs34684955)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012665"
FT VARIANT 157
FT /note="W -> R (in IBD1; unknown pathological 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; unknown pathological significance;
FT dbSNP:rs104895422)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012668"
FT VARIANT 248
FT /note="L -> R (in IBD1; unknown pathological significance;
FT no disruption of NOD2-CARD9 interaction;
FT 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; unknown pathological significance;
FT dbSNP:rs104895424)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012672"
FT VARIANT 294
FT /note="T -> S (in IBD1; unknown pathological significance;
FT dbSNP:rs104895425)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012673"
FT VARIANT 301
FT /note="A -> V (in IBD1; unknown pathological significance;
FT dbSNP:rs104895426)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012674"
FT VARIANT 311
FT /note="R -> W (in IBD1; also found in patients with
FT ulcerative colitis; unknown pathological 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; abolishes
FT interaction with LDOC1, ANKHD1, PPP2R3B, ENTR1 and TRIM41;
FT decreases interaction with RIPK2 and PPP1R12C; no effect on
FT interaction with CHMP5; dbSNP:rs104895461)"
FT /evidence="ECO:0000269|PubMed:11528384,
FT ECO:0000269|PubMed:19116920, ECO:0000269|PubMed:19479837,
FT ECO:0000269|PubMed:25093298, ECO:0000269|PubMed:25724124,
FT 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; dbSNP:rs104895462)"
FT /evidence="ECO:0000269|PubMed:11528384,
FT ECO:0000269|PubMed:15459013, ECO:0000269|PubMed:19116920,
FT ECO:0000269|PubMed:19479837, ECO:0000269|PubMed:20199415,
FT ECO:0000269|PubMed:24960071, ECO:0000269|PubMed:25093298"
FT /id="VAR_012677"
FT VARIANT 348
FT /note="L -> V (in IBD1; unknown pathological significance;
FT dbSNP:rs104895428)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012678"
FT VARIANT 352
FT /note="H -> R (in IBD1; unknown pathological significance;
FT dbSNP:rs5743272)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012679"
FT VARIANT 357
FT /note="D -> A (in IBD1; unknown pathological significance;
FT no disruption of NOD2-CARD9 interaction;
FT 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; unknown pathological significance;
FT no disruption of NOD2-CARD9 interaction;
FT 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; unknown pathological 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; unknown pathological 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; unknown pathological significance;
FT dbSNP:rs104895429)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012681"
FT VARIANT 431
FT /note="S -> L (in IBD1; unknown pathological significance;
FT no disruption of NOD2-CARD9 interaction;
FT 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; unknown pathological significance;
FT dbSNP:rs2076754)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012683"
FT VARIANT 441
FT /note="E -> K (in IBD1; unknown pathological significance;
FT no disruption of NOD2-CARD9 interaction;
FT 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; dbSNP:rs104895460)"
FT /evidence="ECO:0000269|PubMed:11528384,
FT 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; unknown pathological
FT significance; 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; unknown pathological 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; unknown pathological 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 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; unknown pathological significance;
FT no disruption of NOD2-CARD9 interaction;
FT 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; unknown pathological significance;
FT not 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; unknown pathological
FT significance; 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; unknown pathological significance;
FT no disruption of NOD2-CARD9 interaction;
FT 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; unknown pathological 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; no disruption of NOD2-CARD9 interaction;
FT decreases half-life of protein; abolishes interaction with
FT ANKHD1, ENTR1 and TRIM41; increases interaction with RIPK2
FT and PPP2R3B; decreases interaction with LDOC1 and PPP1R12C;
FT no effect on interaction with CHMP5; dbSNP:rs2066844)"
FT /evidence="ECO:0000269|PubMed:11385576,
FT ECO:0000269|PubMed:16485124, ECO:0000269|PubMed:21914217,
FT ECO:0000269|PubMed:24790089, ECO:0000269|PubMed:24960071,
FT ECO:0000269|PubMed:27812135"
FT /id="VAR_012689"
FT VARIANT 703
FT /note="R -> C (in IBD1; also found in patients with
FT ulcerative colitis; unknown pathological 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; unknown pathological significance;
FT dbSNP:rs104895440)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012691"
FT VARIANT 713
FT /note="R -> H (in IBD1; unknown pathological significance;
FT dbSNP:rs104895483)"
FT /evidence="ECO:0000269|PubMed:16485124"
FT /id="VAR_073243"
FT VARIANT 725
FT /note="A -> G (in IBD1; unknown pathological significance;
FT dbSNP:rs5743278)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012692"
FT VARIANT 755
FT /note="A -> V (in IBD1; also found in patients with
FT ulcerative colitis; unknown pathological 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; unknown pathological significance;
FT dbSNP:rs104895442)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012694"
FT VARIANT 760
FT /note="R -> C (in IBD1; unknown pathological significance;
FT dbSNP:rs3813758)"
FT /evidence="ECO:0000269|PubMed:16485124"
FT /id="VAR_073244"
FT VARIANT 778
FT /note="E -> K (in IBD1; unknown pathological 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; unknown pathological 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; unknown pathological 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; unknown pathological 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; unknown pathological significance;
FT dbSNP:rs104895467)"
FT /evidence="ECO:0000269|PubMed:15024686"
FT /id="VAR_073249"
FT VARIANT 853
FT /note="N -> S (in IBD1; unknown pathological significance;
FT dbSNP:rs104895446)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012698"
FT VARIANT 863
FT /note="M -> V (in IBD1; unknown pathological significance;
FT dbSNP:rs104895447)"
FT /evidence="ECO:0000269|PubMed:11385576"
FT /id="VAR_012699"
FT VARIANT 885
FT /note="A -> T (in IBD1; unknown pathological 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; decreases half-life of protein; abolishes
FT interaction with ANKHD1, ENTR1 and TRIM41; decreases
FT interaction with RIPK2 and PPP1R12C; no effect on
FT interaction with CHMP5, LDOC1 and PPP2R3B;
FT dbSNP:rs2066845)"
FT /evidence="ECO:0000269|PubMed:11087742,
FT ECO:0000269|PubMed:11385576, 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; unknown pathological 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 MUTAGEN 305
FT /note="K->R: No activation."
FT /evidence="ECO:0000269|PubMed:11087742"
FT MUTAGEN 379
FT /note="D->A: No disruption in NOD2-CARD9 interaction."
FT /evidence="ECO:0000269|PubMed:24960071"
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
