P25092 (GUC2C_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Heat-stable enterotoxin receptor
Short name=STA receptor
Short name=hSTAR
EC=4.6.1.2

Alternative name(s):
Guanylyl cyclase C
Short name=GC-C
Intestinal guanylate cyclase

Gene names

Name:	GUCY2C
Synonyms:	GUC2C, STAR

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1073 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Receptor for the E.coli heat-stable enterotoxin (E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GC-C). Also activated by the endogenous peptide guanylin.
Catalytic activity	GTP = 3',5'-cyclic GMP + diphosphate.
Subunit structure	Homotrimer. Interacts via its C-terminal region with PDZK2. Ref.8 Ref.9
Subcellular location	Membrane; Single-pass type I membrane protein.
Domain	The protein kinase domain is predicted to be catalytically inactive.
Involvement in disease	Diarrhea 6 (DIAR6) [MIM:614616]: A relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 Meconium ileus (MECIL) [MIM:614665]: A condition characterized by a intestinal obstruction due to inspissated meconium in the distal ileum and cecum, which develops in utero and presents shortly after birth as a failure to pass meconium. Meconium ileus is a known clinical manifestation of cystic fibrosis. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10
Sequence similarities	Belongs to the adenylyl cyclase class-4/guanylyl cyclase family. Contains 1 guanylate cyclase domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	cGMP biosynthesis
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	Signal Transmembrane Transmembrane helix
Ligand	GTP-binding Nucleotide-binding
Molecular function	Lyase Receptor
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	intracellular signal transduction Inferred from electronic annotation. Source: InterPro receptor guanylyl cyclase signaling pathway Traceable author statement Ref.2. Source: ProtInc regulation of cell proliferation Inferred from electronic annotation. Source: Compara response to toxin Inferred from electronic annotation. Source: Compara
Cellular_component	integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	ATP binding Inferred from electronic annotation. Source: InterPro GTP binding Inferred from electronic annotation. Source: UniProtKB-KW guanylate cyclase activity Traceable author statement Ref.2. Source: ProtInc protein kinase activity Inferred from electronic annotation. Source: InterPro toxin binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 23	23	Potential
	Chain	24 – 1073	1050	Heat-stable enterotoxin receptor		PRO_0000012376
Regions
	Topological domain	24 – 430	407	Extracellular Potential
	Transmembrane	431 – 454	24	Helical; Potential
	Topological domain	455 – 1073	619	Cytoplasmic Potential
	Domain	489 – 749	261	Protein kinase
	Domain	824 – 954	131	Guanylate cyclase
Amino acid modifications
	Glycosylation	32	1	N-linked (GlcNAc...) Potential
	Glycosylation	75	1	N-linked (GlcNAc...) Potential
	Glycosylation	79	1	N-linked (GlcNAc...) Potential
	Glycosylation	195	1	N-linked (GlcNAc...) Potential
	Glycosylation	284	1	N-linked (GlcNAc...) Potential
	Glycosylation	307	1	N-linked (GlcNAc...) Potential
	Glycosylation	345	1	N-linked (GlcNAc...) Potential
	Glycosylation	357	1	N-linked (GlcNAc...) Potential
	Glycosylation	402	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	30	1	C → R. Ref.12 Corresponds to variant rs56142849 [ dbSNP | Ensembl ].		VAR_042221
	Natural variant	61	1	G → R in a metastatic melanoma sample; somatic mutation. Ref.12		VAR_042222
	Natural variant	114	1	R → Q. Ref.12 Corresponds to variant rs56275235 [ dbSNP | Ensembl ].		VAR_042223
	Natural variant	281	1	F → L. Ref.1 Ref.2 Ref.4 Ref.5 Ref.7 Corresponds to variant rs1420635 [ dbSNP | Ensembl ].		VAR_049253
	Natural variant	387	1	D → G in MECIL; activation of guanylate cyclase activity is 60% lower than in wild-type. Ref.10		VAR_068174
	Natural variant	464	1	R → L. Ref.12 Corresponds to variant rs55684775 [ dbSNP | Ensembl ].		VAR_042224
	Natural variant	610	1	E → K. Ref.12 Corresponds to variant rs55897626 [ dbSNP | Ensembl ].		VAR_042225
	Natural variant	840	1	S → I in DIAR6; activating mutation; exposure of the mutant receptor to its ligands results in markedly increased production of cyclic guanosine monophosphate. Ref.11		VAR_067724
	Natural variant	859	1	I → V. Ref.12 Corresponds to variant rs34890806 [ dbSNP | Ensembl ].		VAR_042226
	Natural variant	1045	1	Q → R. Ref.12 Corresponds to variant rs35617837 [ dbSNP | Ensembl ].		VAR_042227
	Natural variant	1072	1	Y → C. Ref.12 Corresponds to variant rs35179392 [ dbSNP | Ensembl ].		VAR_042228
Experimental info
	Sequence conflict	322	1	A → R in AAB19934. Ref.1
	Sequence conflict	331	1	L → V in AAB19934. Ref.1
	Sequence conflict	509	1	D → V in AAB19934. Ref.1
	Sequence conflict	543	1	N → T in AAB19934. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P25092 [UniParc]. Last modified November 2, 2010. Version 2. Checksum: 486A4DE6F9097E22	FASTA	1,073	123,403
	10 20 30 40 50 60 MKTLLLDLAL WSLLFQPGWL SFSSQVSQNC HNGSYEISVL MMGNSAFAEP LKNLEDAVNE 70 80 90 100 110 120 GLEIVRGRLQ NAGLNVTVNA TFMYSDGLIH NSGDCRSSTC EGLDLLRKIS NAQRMGCVLI 130 140 150 160 170 180 GPSCTYSTFQ MYLDTELSYP MISAGSFGLS CDYKETLTRL MSPARKLMYF LVNFWKTNDL 190 200 210 220 230 240 PFKTYSWSTS YVYKNGTETE DCFWYLNALE ASVSYFSHEL GFKVVLRQDK EFQDILMDHN 250 260 270 280 290 300 RKSNVIIMCG GPEFLYKLKG DRAVAEDIVI ILVDLFNDQY FEDNVTAPDY MKNVLVLTLS 310 320 330 340 350 360 PGNSLLNSSF SRNLSPTKRD FALAYLNGIL LFGHMLKIFL ENGENITTPK FAHAFRNLTF 370 380 390 400 410 420 EGYDGPVTLD DWGDVDSTMV LLYTSVDTKK YKVLLTYDTH VNKTYPVDMS PTFTWKNSKL 430 440 450 460 470 480 PNDITGRGPQ ILMIAVFTLT GAVVLLLLVA LLMLRKYRKD YELRQKKWSH IPPENIFPLE 490 500 510 520 530 540 TNETNHVSLK IDDDKRRDTI QRLRQCKYDK KRVILKDLKH NDGNFTEKQK IELNKLLQID 550 560 570 580 590 600 YYNLTKFYGT VKLDTMIFGV IEYCERGSLR EVLNDTISYP DGTFMDWEFK ISVLYDIAKG 610 620 630 640 650 660 MSYLHSSKTE VHGRLKSTNC VVDSRMVVKI TDFGCNSILP PKKDLWTAPE HLRQANISQK 670 680 690 700 710 720 GDVYSYGIIA QEIILRKETF YTLSCRDRNE KIFRVENSNG MKPFRPDLFL ETAEEKELEV 730 740 750 760 770 780 YLLVKNCWEE DPEKRPDFKK IETTLAKIFG LFHDQKNESY MDTLIRRLQL YSRNLEHLVE 790 800 810 820 830 840 ERTQLYKAER DRADRLNFML LPRLVVKSLK EKGFVEPELY EEVTIYFSDI VGFTTICKYS 850 860 870 880 890 900 TPMEVVDMLN DIYKSFDHIV DHHDVYKVET IGDAYMVASG LPKRNGNRHA IDIAKMALEI 910 920 930 940 950 960 LSFMGTFELE HLPGLPIWIR IGVHSGPCAA GVVGIKMPRY CLFGDTVNTA SRMESTGLPL 970 980 990 1000 1010 1020 RIHVSGSTIA ILKRTECQFL YEVRGETYLK GRGNETTYWL TGMKDQKFNL PTPPTVENQQ 1030 1040 1050 1060 1070 RLQAEFSDMI ANSLQKRQAA GIRSQKPRRV ASYKKGTLEY LQLNTTDKES TYF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and expression of a guanylate cyclase-coupled heat stable enterotoxin receptor cDNA from a human colonic cell line." Singh S., Singh G., Heim J.-M., Gerzer R. Biochem. Biophys. Res. Commun. 179:1455-1463(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT LEU-281.
[2]	"Primary structure and functional expression of the human receptor for Escherichia coli heat-stable enterotoxin." de Sauvage F.J., Camerato T.R., Goeddel D.V. J. Biol. Chem. 266:17912-17918(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT LEU-281.
[3]	"The finished DNA sequence of human chromosome 12." Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A. Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT LEU-281.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT LEU-281.
[6]	"Cell line-specific transcriptional activation of the promoter of the human guanylyl cyclase C/heat-stable enterotoxin receptor gene." Mann E.A., Jump M.L., Giannella R.A. Biochim. Biophys. Acta 1305:7-10(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-72. Tissue: Placenta.
[7]	"Comparison of receptors for Escherichia coli heat-stable enterotoxin: novel receptor present in IEC-6 cells." Mann E.A., Cohen M.B., Giannella R.A. Am. J. Physiol. 264:G172-G178(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 24-1073, VARIANT LEU-281. Tissue: Colon carcinoma.
[8]	"Biochemical characterization of the intracellular domain of the human guanylyl cyclase C receptor provides evidence for a catalytically active homotrimer." Vijayachandra K., Guruprasad M., Bhandari R., Manjunath U.H., Somesh B.P., Srinivasan N., Suguna K., Visweswariah S.S. Biochemistry 39:16075-16083(2000) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT.
[9]	"A novel PDZ protein regulates the activity of guanylyl cyclase C, the heat-stable enterotoxin receptor." Scott R.O., Thelin W.R., Milgram S.L. J. Biol. Chem. 277:22934-22941(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PDZK2.
[10]	"Meconium ileus caused by mutations in GUCY2C, encoding the CFTR-activating guanylate cyclase 2C." Romi H., Cohen I., Landau D., Alkrinawi S., Yerushalmi B., Hershkovitz R., Newman-Heiman N., Cutting G.R., Ofir R., Sivan S., Birk O.S. Am. J. Hum. Genet. 90:893-899(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT MECIL GLY-387, CHARACTERIZATION OF VARIANT MECIL GLY-387.
[11]	"Familial diarrhea syndrome caused by an activating GUCY2C mutation." Fiskerstrand T., Arshad N., Haukanes B.I., Tronstad R.R., Pham K.D., Johansson S., Havik B., Tonder S.L., Levy S.E., Brackman D., Boman H., Biswas K.H., Apold J., Hovdenak N., Visweswariah S.S., Knappskog P.M. N. Engl. J. Med. 366:1586-1595(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT DIAR6 ILE-840, CHARACTERIZATION OF VARIANT DIAR6 ILE-840.
[12]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] ARG-30; ARG-61; GLN-114; LEU-464; LYS-610; VAL-859; ARG-1045 AND CYS-1072.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	S57551 mRNA. Translation: AAB19934.2. M73489 mRNA. Translation: AAA36655.1. AC007545 Genomic DNA. No translation available. AC010168 Genomic DNA. No translation available. CH471094 Genomic DNA. Translation: EAW96324.1. BC136544 mRNA. Translation: AAI36545.1. BC136545 mRNA. Translation: AAI36546.1. U20230 Genomic DNA. Translation: AAC50381.1.
IPI	IPI00012491.
PIR	OYHUHX. A40940.
RefSeq	NP_004954.2. NM_004963.3.
UniGene	Hs.524278.
3D structure databases
ProteinModelPortal	P25092.
SMR	P25092. Positions 490-773, 815-1001.
ModBase	Search...
Protein-protein interaction databases
IntAct	P25092. 1 interaction.
MINT	MINT-261763.
STRING	9606.ENSP00000261170.
PTM databases
PhosphoSite	P25092.
Polymorphism databases
DMDM	311033390.
Proteomic databases
PaxDb	P25092.
PRIDE	P25092.
Protocols and materials databases
DNASU	2984.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000261170; ENSP00000261170; ENSG00000070019.
GeneID	2984.
KEGG	hsa:2984.
UCSC	uc001rcd.3. human.
Organism-specific databases
CTD	2984.
GeneCards	GC12M014765.
H-InvDB	HIX0036867.
HGNC	HGNC:4688. GUCY2C.
HPA	HPA037655.
MIM	601330. gene. 614616. phenotype. 614665. phenotype.
neXtProt	NX_P25092.
PharmGKB	PA29069.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000112833.
HOVERGEN	HBG106967.
InParanoid	P25092.
KO	K12320.
OMA	APDYMKN.
OrthoDB	EOG447FSH.
PhylomeDB	P25092.
Gene expression databases
Bgee	P25092.
CleanEx	HS_GUCY2C. HS_STAR.
Genevestigator	P25092.
GermOnline	ENSG00000070019. Homo sapiens.
Family and domain databases
Gene3D	3.30.70.1230. 1 hit.
InterPro	IPR001054. A/G_cyclase. IPR018297. A/G_cyclase_CS. IPR001828. ANF_lig-bd_rcpt. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. [Graphical view]
Pfam	PF01094. ANF_receptor. 1 hit. PF00211. Guanylate_cyc. 1 hit. PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
SMART	SM00044. CYCc. 1 hit. [Graphical view]
SUPFAM	SSF55073. A/G_cyclase. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS00452. GUANYLATE_CYCLASE_1. 1 hit. PS50125. GUANYLATE_CYCLASE_2. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChEMBL	CHEMBL1795197.
GenomeRNAi	2984.
NextBio	11836.
SOURCE	Search...

Entry information

Entry name

GUC2C_HUMAN

Accession

Primary (citable) accession number: P25092
Secondary accession number(s): B2RMY6

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1992
Last sequence update:	November 2, 2010
Last modified:	May 1, 2013
This is version 140 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.