ID GUC2C_HUMAN Reviewed; 1073 AA. AC P25092; B2RMY6; DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 2. DT 27-MAR-2024, entry version 217. DE RecName: Full=Guanylyl cyclase C {ECO:0000303|PubMed:11950846}; DE Short=GC-C {ECO:0000303|PubMed:11950846}; DE EC=4.6.1.2 {ECO:0000269|PubMed:11950846, ECO:0000269|PubMed:23269669, ECO:0000305|PubMed:1718270}; DE AltName: Full=Heat-stable enterotoxin receptor {ECO:0000303|PubMed:1718270}; DE Short=STA receptor {ECO:0000303|PubMed:1718270}; DE Short=hSTAR {ECO:0000303|PubMed:1718270}; DE AltName: Full=Intestinal guanylate cyclase; DE Flags: Precursor; GN Name=GUCY2C {ECO:0000303|PubMed:22521417, ECO:0000312|HGNC:HGNC:4688}; GN Synonyms=GUC2C, STAR {ECO:0000303|PubMed:1718270}; 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], FUNCTION, CATALYTIC ACTIVITY, AND VARIANT RP LEU-281. RX PubMed=1718270; DOI=10.1016/0006-291x(91)91736-v; RA Singh S., Singh G., Heim J.-M., Gerzer R.; RT "Isolation and expression of a guanylate cyclase-coupled heat stable RT enterotoxin receptor cDNA from a human colonic cell line."; RL Biochem. Biophys. Res. Commun. 179:1455-1463(1991). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND VARIANT LEU-281. RX PubMed=1680854; DOI=10.1016/s0021-9258(18)55214-5; RA de Sauvage F.J., Camerato T.R., Goeddel D.V.; RT "Primary structure and functional expression of the human receptor for RT Escherichia coli heat-stable enterotoxin."; RL J. Biol. Chem. 266:17912-17918(1991). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT LEU-281. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LEU-281. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72. RC TISSUE=Placenta; RX PubMed=8605253; DOI=10.1016/0167-4781(95)00190-5; RA Mann E.A., Jump M.L., Giannella R.A.; RT "Cell line-specific transcriptional activation of the promoter of the human RT guanylyl cyclase C/heat-stable enterotoxin receptor gene."; RL Biochim. Biophys. Acta 1305:7-10(1996). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 24-1073, FUNCTION, AND VARIANT RP LEU-281. RC TISSUE=Colon carcinoma; RX PubMed=8381596; DOI=10.1152/ajpgi.1993.264.1.g172; RA Mann E.A., Cohen M.B., Giannella R.A.; RT "Comparison of receptors for Escherichia coli heat-stable enterotoxin: RT novel receptor present in IEC-6 cells."; RL Am. J. Physiol. 264:G172-G178(1993). RN [8] RP SUBUNIT. RX PubMed=11123935; DOI=10.1021/bi0013849; RA Vijayachandra K., Guruprasad M., Bhandari R., Manjunath U.H., Somesh B.P., RA Srinivasan N., Suguna K., Visweswariah S.S.; RT "Biochemical characterization of the intracellular domain of the human RT guanylyl cyclase C receptor provides evidence for a catalytically active RT homotrimer."; RL Biochemistry 39:16075-16083(2000). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH NHERF4. RX PubMed=11950846; DOI=10.1074/jbc.m202434200; RA Scott R.O., Thelin W.R., Milgram S.L.; RT "A novel PDZ protein regulates the activity of guanylyl cyclase C, the RT heat-stable enterotoxin receptor."; RL J. Biol. Chem. 277:22934-22941(2002). RN [10] RP GLYCOSYLATION AT ASN-32; ASN-75; ASN-79; ASN-195; ASN-284; ASN-307; ASN-345 RP AND ASN-402, LACK OF GLYCOSYLATION AT ASN-357, FUNCTION, CATALYTIC RP ACTIVITY, INTERACTION WITH VIP36, AND SUBCELLULAR LOCATION. RX PubMed=23269669; DOI=10.1074/jbc.m112.413906; RA Arshad N., Ballal S., Visweswariah S.S.; RT "Site-specific N-linked glycosylation of receptor guanylyl cyclase C RT regulates ligand binding, ligand-mediated activation and interaction with RT vesicular integral membrane protein 36, VIP36."; RL J. Biol. Chem. 288:3907-3917(2013). RN [11] RP VARIANT MECIL GLY-387, FUNCTION, AND CHARACTERIZATION OF VARIANT MECIL RP GLY-387. RX PubMed=22521417; DOI=10.1016/j.ajhg.2012.03.022; RA Romi H., Cohen I., Landau D., Alkrinawi S., Yerushalmi B., Hershkovitz R., RA Newman-Heiman N., Cutting G.R., Ofir R., Sivan S., Birk O.S.; RT "Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating RT guanylate cyclase 2C."; RL Am. J. Hum. Genet. 90:893-899(2012). RN [12] RP VARIANT DIAR6 ILE-840, FUNCTION, AND CHARACTERIZATION OF VARIANT DIAR6 RP ILE-840. RX PubMed=22436048; DOI=10.1056/nejmoa1110132; RA Fiskerstrand T., Arshad N., Haukanes B.I., Tronstad R.R., Pham K.D., RA Johansson S., Havik B., Tonder S.L., Levy S.E., Brackman D., Boman H., RA Biswas K.H., Apold J., Hovdenak N., Visweswariah S.S., Knappskog P.M.; RT "Familial diarrhea syndrome caused by an activating GUCY2C mutation."; RL N. Engl. J. Med. 366:1586-1595(2012). RN [13] RP VARIANTS [LARGE SCALE ANALYSIS] ARG-30; ARG-61; GLN-114; LEU-464; LYS-610; RP VAL-859; ARG-1045 AND CYS-1072. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G., RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., RA Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). CC -!- FUNCTION: Guanylyl cyclase that catalyzes synthesis of cyclic GMP CC (cGMP) from GTP (PubMed:1718270, PubMed:11950846, PubMed:23269669, CC PubMed:22521417, PubMed:22436048). Receptor for the E.coli heat-stable CC enterotoxin; E.coli enterotoxin markedly stimulates the accumulation of CC cGMP in mammalian cells expressing GUCY2C (PubMed:1718270, CC PubMed:1680854). Also activated by the endogenous peptides guanylin and CC uroguanylin (PubMed:8381596). {ECO:0000269|PubMed:11950846, CC ECO:0000269|PubMed:1680854, ECO:0000269|PubMed:1718270, CC ECO:0000269|PubMed:22436048, ECO:0000269|PubMed:22521417, CC ECO:0000269|PubMed:23269669, ECO:0000269|PubMed:8381596}. CC -!- CATALYTIC ACTIVITY: CC Reaction=GTP = 3',5'-cyclic GMP + diphosphate; Xref=Rhea:RHEA:13665, CC ChEBI:CHEBI:33019, ChEBI:CHEBI:37565, ChEBI:CHEBI:57746; EC=4.6.1.2; CC Evidence={ECO:0000269|PubMed:11950846, ECO:0000269|PubMed:23269669, CC ECO:0000305|PubMed:1718270}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:13666; CC Evidence={ECO:0000269|PubMed:11950846, ECO:0000305|PubMed:1718270}; CC -!- SUBUNIT: Homotrimer (PubMed:11123935). Interacts via its C-terminal CC region with NHERF4 (PubMed:11950846). Interacts with the lectin CC chaperone VIP36 (PubMed:23269669). {ECO:0000269|PubMed:11123935, CC ECO:0000269|PubMed:11950846, ECO:0000269|PubMed:23269669}. CC -!- INTERACTION: CC P25092; Q86UT5-2: NHERF4; NbExp=4; IntAct=EBI-2816795, EBI-8299496; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23269669}; CC Single-pass type I membrane protein {ECO:0000269|PubMed:23269669}. CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:23269669}; Single- CC pass type I membrane protein {ECO:0000269|PubMed:23269669}. Note=The CC 145 kDa plasma membrane form of GUCY2C contains sialic acid and CC galactose residues, while a differencially glycosylated 130 Kda form is CC a high mannose form that is resident in the endoplasmic reticulum and CC may serve as the precursor for the cell surface form. CC {ECO:0000269|PubMed:23269669}. CC -!- DOMAIN: The protein kinase domain is predicted to be catalytically CC inactive. CC -!- PTM: Glycosylation at Asn-75 and/or Asn-79 is required for interaction CC with VIP36 while glycosylation at Asn-345 and Asn-402 modulates ligand- CC mediated GUCY2C activation. {ECO:0000269|PubMed:23269669}. CC -!- DISEASE: Diarrhea 6 (DIAR6) [MIM:614616]: A relatively mild, early- CC onset chronic diarrhea that may be associated with increased CC susceptibility to inflammatory bowel disease, small bowel obstruction, CC and esophagitis. {ECO:0000269|PubMed:22436048}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- DISEASE: Meconium ileus (MECIL) [MIM:614665]: A condition characterized CC by intestinal obstruction due to inspissated meconium in the distal CC ileum and cecum, which develops in utero and presents shortly after CC birth as a failure to pass meconium. Meconium ileus is a known clinical CC manifestation of cystic fibrosis. {ECO:0000269|PubMed:22521417}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/43303/GUCY2C"; 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; S57551; AAB19934.2; -; mRNA. DR EMBL; M73489; AAA36655.1; -; mRNA. DR EMBL; AC007545; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC010168; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471094; EAW96324.1; -; Genomic_DNA. DR EMBL; BC136544; AAI36545.1; -; mRNA. DR EMBL; BC136545; AAI36546.1; -; mRNA. DR EMBL; U20230; AAC50381.1; -; Genomic_DNA. DR CCDS; CCDS8664.1; -. DR PIR; A40940; OYHUHX. DR RefSeq; NP_004954.2; NM_004963.3. DR PDB; 8FX4; EM; 3.90 A; D=419-1073. DR PDB; 8GHO; X-ray; 1.60 A; C/G=93-110. DR PDB; 8GHP; X-ray; 3.52 A; A=24-430. DR PDBsum; 8FX4; -. DR PDBsum; 8GHO; -. DR PDBsum; 8GHP; -. DR AlphaFoldDB; P25092; -. DR EMDB; EMD-29523; -. DR SMR; P25092; -. DR BioGRID; 109239; 2. DR IntAct; P25092; 3. DR MINT; P25092; -. DR STRING; 9606.ENSP00000261170; -. DR ChEMBL; CHEMBL1795197; -. DR DrugBank; DB08890; Linaclotide. DR DrugCentral; P25092; -. DR GuidetoPHARMACOLOGY; 1750; -. DR TCDB; 8.A.85.1.1; the guanylate cyclase (gc) family. DR GlyCosmos; P25092; 8 sites, No reported glycans. DR GlyGen; P25092; 8 sites. DR iPTMnet; P25092; -. DR PhosphoSitePlus; P25092; -. DR BioMuta; GUCY2C; -. DR DMDM; 311033390; -. DR jPOST; P25092; -. DR MassIVE; P25092; -. DR MaxQB; P25092; -. DR PaxDb; 9606-ENSP00000261170; -. DR PeptideAtlas; P25092; -. DR ProteomicsDB; 54253; -. DR ABCD; P25092; 1 sequenced antibody. DR Antibodypedia; 12046; 319 antibodies from 26 providers. DR DNASU; 2984; -. DR Ensembl; ENST00000261170.5; ENSP00000261170.3; ENSG00000070019.5. DR GeneID; 2984; -. DR KEGG; hsa:2984; -. DR MANE-Select; ENST00000261170.5; ENSP00000261170.3; NM_004963.4; NP_004954.2. DR UCSC; uc001rcd.4; human. DR AGR; HGNC:4688; -. DR CTD; 2984; -. DR DisGeNET; 2984; -. DR GeneCards; GUCY2C; -. DR HGNC; HGNC:4688; GUCY2C. DR HPA; ENSG00000070019; Tissue enriched (intestine). DR MalaCards; GUCY2C; -. DR MIM; 601330; gene. DR MIM; 614616; phenotype. DR MIM; 614665; phenotype. DR neXtProt; NX_P25092; -. DR OpenTargets; ENSG00000070019; -. DR Orphanet; 314373; Chronic infantile diarrhea due to guanylate cyclase 2C overactivity. DR Orphanet; 103908; Congenital sodium diarrhea. DR Orphanet; 314376; Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency. DR PharmGKB; PA29069; -. DR VEuPathDB; HostDB:ENSG00000070019; -. DR eggNOG; KOG1023; Eukaryota. DR GeneTree; ENSGT00940000155955; -. DR HOGENOM; CLU_001072_1_3_1; -. DR InParanoid; P25092; -. DR OMA; VNFWKAN; -. DR OrthoDB; 3683909at2759; -. DR PhylomeDB; P25092; -. DR BRENDA; 4.6.1.2; 2681. DR PathwayCommons; P25092; -. DR Reactome; R-HSA-8935690; Digestion. DR Reactome; R-HSA-8942233; Intestinal infectious diseases. DR SignaLink; P25092; -. DR SIGNOR; P25092; -. DR BioGRID-ORCS; 2984; 7 hits in 1163 CRISPR screens. DR ChiTaRS; GUCY2C; human. DR GeneWiki; Guanylate_cyclase_2C; -. DR GenomeRNAi; 2984; -. DR Pharos; P25092; Tclin. DR PRO; PR:P25092; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; P25092; Protein. DR Bgee; ENSG00000070019; Expressed in jejunal mucosa and 60 other cell types or tissues. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0004016; F:adenylate cyclase activity; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:InterPro. DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW. DR GO; GO:0004383; F:guanylate cyclase activity; IDA:UniProtKB. DR GO; GO:0001653; F:peptide receptor activity; IBA:GO_Central. DR GO; GO:0004672; F:protein kinase activity; IEA:InterPro. DR GO; GO:0015643; F:toxic substance binding; IEA:Ensembl. DR GO; GO:0006182; P:cGMP biosynthetic process; IBA:GO_Central. DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro. DR GO; GO:0007168; P:receptor guanylyl cyclase signaling pathway; IBA:GO_Central. DR GO; GO:0042127; P:regulation of cell population proliferation; IEA:Ensembl. DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl. DR CDD; cd07302; CHD; 1. DR CDD; cd06369; PBP1_GC_C_enterotoxin_receptor; 1. DR CDD; cd14044; PK_GC-C; 1. DR Gene3D; 3.40.50.2300; -; 1. DR Gene3D; 3.30.70.1230; Nucleotide cyclase; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR001054; A/G_cyclase. DR InterPro; IPR018297; A/G_cyclase_CS. DR InterPro; IPR042822; GC-C_PK. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR029787; Nucleotide_cyclase. DR InterPro; IPR028082; Peripla_BP_I. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR PANTHER; PTHR11920; GUANYLYL CYCLASE; 1. DR PANTHER; PTHR11920:SF347; GUANYLYL CYCLASE C; 1. DR Pfam; PF00211; Guanylate_cyc; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR SMART; SM00044; CYCc; 1. DR SUPFAM; SSF55073; Nucleotide cyclase; 1. DR SUPFAM; SSF53822; Periplasmic binding protein-like I; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 1. DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR Genevisible; P25092; HS. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; cGMP biosynthesis; Disease variant; KW Endoplasmic reticulum; Glycoprotein; GTP-binding; Lyase; Membrane; KW Nucleotide-binding; Receptor; Reference proteome; Signal; Transmembrane; KW Transmembrane helix. FT SIGNAL 1..23 FT /evidence="ECO:0000255" FT CHAIN 24..1073 FT /note="Guanylyl cyclase C" FT /id="PRO_0000012376" FT TOPO_DOM 24..430 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 431..454 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 455..1073 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 489..749 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 824..954 FT /note="Guanylate cyclase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099" FT SITE 357 FT /note="Not glycosylated" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 32 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 75 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 79 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 195 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 284 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 307 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 345 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT CARBOHYD 402 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:23269669" FT VARIANT 30 FT /note="C -> R (in dbSNP:rs56142849)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042221" FT VARIANT 61 FT /note="G -> R (in a metastatic melanoma sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042222" FT VARIANT 114 FT /note="R -> Q (in dbSNP:rs56275235)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042223" FT VARIANT 281 FT /note="F -> L (in dbSNP:rs1420635)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:1680854, ECO:0000269|PubMed:1718270, FT ECO:0000269|PubMed:8381596, ECO:0000269|Ref.4" FT /id="VAR_049253" FT VARIANT 387 FT /note="D -> G (in MECIL; activation of guanylate cyclase FT activity is 60% lower than in wild-type; FT dbSNP:rs587776905)" FT /evidence="ECO:0000269|PubMed:22521417" FT /id="VAR_068174" FT VARIANT 464 FT /note="R -> L (in dbSNP:rs55684775)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042224" FT VARIANT 610 FT /note="E -> K (in dbSNP:rs55897626)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042225" FT VARIANT 840 FT /note="S -> I (in DIAR6; activating mutation; exposure of FT the mutant receptor to its ligands results in markedly FT increased production of cyclic guanosine monophosphate; FT dbSNP:rs587776871)" FT /evidence="ECO:0000269|PubMed:22436048" FT /id="VAR_067724" FT VARIANT 859 FT /note="I -> V (in dbSNP:rs34890806)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042226" FT VARIANT 1045 FT /note="Q -> R (in dbSNP:rs35617837)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042227" FT VARIANT 1072 FT /note="Y -> C (in dbSNP:rs35179392)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042228" FT CONFLICT 322 FT /note="A -> R (in Ref. 1; AAB19934)" FT /evidence="ECO:0000305" FT CONFLICT 331 FT /note="L -> V (in Ref. 1; AAB19934)" FT /evidence="ECO:0000305" FT CONFLICT 509 FT /note="D -> V (in Ref. 1; AAB19934)" FT /evidence="ECO:0000305" FT CONFLICT 543 FT /note="N -> T (in Ref. 1; AAB19934)" FT /evidence="ECO:0000305" FT HELIX 98..108 FT /evidence="ECO:0007829|PDB:8GHO" SQ SEQUENCE 1073 AA; 123403 MW; 486A4DE6F9097E22 CRC64; MKTLLLDLAL WSLLFQPGWL SFSSQVSQNC HNGSYEISVL MMGNSAFAEP LKNLEDAVNE GLEIVRGRLQ NAGLNVTVNA TFMYSDGLIH NSGDCRSSTC EGLDLLRKIS NAQRMGCVLI GPSCTYSTFQ MYLDTELSYP MISAGSFGLS CDYKETLTRL MSPARKLMYF LVNFWKTNDL PFKTYSWSTS YVYKNGTETE DCFWYLNALE ASVSYFSHEL GFKVVLRQDK EFQDILMDHN RKSNVIIMCG GPEFLYKLKG DRAVAEDIVI ILVDLFNDQY FEDNVTAPDY MKNVLVLTLS PGNSLLNSSF SRNLSPTKRD FALAYLNGIL LFGHMLKIFL ENGENITTPK FAHAFRNLTF EGYDGPVTLD DWGDVDSTMV LLYTSVDTKK YKVLLTYDTH VNKTYPVDMS PTFTWKNSKL PNDITGRGPQ ILMIAVFTLT GAVVLLLLVA LLMLRKYRKD YELRQKKWSH IPPENIFPLE TNETNHVSLK IDDDKRRDTI QRLRQCKYDK KRVILKDLKH NDGNFTEKQK IELNKLLQID YYNLTKFYGT VKLDTMIFGV IEYCERGSLR EVLNDTISYP DGTFMDWEFK ISVLYDIAKG MSYLHSSKTE VHGRLKSTNC VVDSRMVVKI TDFGCNSILP PKKDLWTAPE HLRQANISQK GDVYSYGIIA QEIILRKETF YTLSCRDRNE KIFRVENSNG MKPFRPDLFL ETAEEKELEV YLLVKNCWEE DPEKRPDFKK IETTLAKIFG LFHDQKNESY MDTLIRRLQL YSRNLEHLVE ERTQLYKAER DRADRLNFML LPRLVVKSLK EKGFVEPELY EEVTIYFSDI VGFTTICKYS TPMEVVDMLN DIYKSFDHIV DHHDVYKVET IGDAYMVASG LPKRNGNRHA IDIAKMALEI LSFMGTFELE HLPGLPIWIR IGVHSGPCAA GVVGIKMPRY CLFGDTVNTA SRMESTGLPL RIHVSGSTIA ILKRTECQFL YEVRGETYLK GRGNETTYWL TGMKDQKFNL PTPPTVENQQ RLQAEFSDMI ANSLQKRQAA GIRSQKPRRV ASYKKGTLEY LQLNTTDKES TYF //