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Protein

Heat-stable enterotoxin receptor

Gene

GUCY2C

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 peptides guanylin and uroguanylin.

Catalytic activityi

GTP = 3',5'-cyclic GMP + diphosphate.

GO - Molecular functioni

  • ATP binding Source: InterPro
  • GTP binding Source: UniProtKB-KW
  • guanylate cyclase activity Source: ProtInc
  • protein kinase activity Source: InterPro
  • toxic substance binding Source: Ensembl

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Lyase, Receptor

Keywords - Biological processi

cGMP biosynthesis

Keywords - Ligandi

GTP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS00979-MONOMER.
BRENDAi4.6.1.2. 2681.
SIGNORiP25092.

Protein family/group databases

TCDBi8.A.85.1.1. the guanylate cyclase (gc) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Heat-stable enterotoxin receptor (EC:4.6.1.2)
Short name:
STA receptor
Short name:
hSTAR
Alternative name(s):
Guanylyl cyclase C
Short name:
GC-C
Intestinal guanylate cyclase
Gene namesi
Name:GUCY2C
Synonyms:GUC2C, STAR
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:4688. GUCY2C.

Subcellular locationi

  • Cell membrane 1 Publication; Single-pass type I membrane protein 1 Publication
  • Endoplasmic reticulum membrane 1 Publication; Single-pass type I membrane protein 1 Publication

  • Note: The 145 kDa plasma membrane form of GC-C contains sialic acid and galactose residues, while a differencially glycosylated 130 Kda form is a high mannose form that is resident in the endoplasmic reticulum and may serve as the precursor for the cell surface form.

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini24 – 430ExtracellularSequence analysisAdd BLAST407
Transmembranei431 – 454HelicalSequence analysisAdd BLAST24
Topological domaini455 – 1073CytoplasmicSequence analysisAdd BLAST619

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endoplasmic reticulum, Membrane

Pathology & Biotechi

Involvement in diseasei

Diarrhea 6 (DIAR6)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis.
See also OMIM:614616
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067724840S → I in DIAR6; activating mutation; exposure of the mutant receptor to its ligands results in markedly increased production of cyclic guanosine monophosphate. 1 PublicationCorresponds to variant rs587776871dbSNPEnsembl.1
Meconium ileus (MECIL)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:614665
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068174387D → G in MECIL; activation of guanylate cyclase activity is 60% lower than in wild-type. 1 PublicationCorresponds to variant rs587776905dbSNPEnsembl.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi2984.
MalaCardsiGUCY2C.
MIMi614616. phenotype.
614665. phenotype.
OpenTargetsiENSG00000070019.
Orphaneti314373. Chronic diarrhea due to guanylate cyclase 2C overactivity.
314376. Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency.
PharmGKBiPA29069.

Chemistry databases

ChEMBLiCHEMBL1795197.
DrugBankiDB08890. Linaclotide.
GuidetoPHARMACOLOGYi1750.

Polymorphism and mutation databases

BioMutaiGUCY2C.
DMDMi311033390.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 23Sequence analysisAdd BLAST23
ChainiPRO_000001237624 – 1073Heat-stable enterotoxin receptorAdd BLAST1050

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi32N-linked (GlcNAc...)1 Publication1
Glycosylationi75N-linked (GlcNAc...)1 Publication1
Glycosylationi79N-linked (GlcNAc...)1 Publication1
Glycosylationi195N-linked (GlcNAc...)1 Publication1
Glycosylationi284N-linked (GlcNAc...)1 Publication1
Glycosylationi307N-linked (GlcNAc...)1 Publication1
Glycosylationi345N-linked (GlcNAc...)1 Publication1
Glycosylationi402N-linked (GlcNAc...)1 Publication1

Post-translational modificationi

Glycosylation at Asn-75 and/or Asn-79 is required for interaction with VIP36 while glycosylation at Asn-345 and Asn-402 modulates ligand-mediated GC-C activation.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei357Not glycosylated1

Keywords - PTMi

Glycoprotein

Proteomic databases

MaxQBiP25092.
PaxDbiP25092.
PeptideAtlasiP25092.
PRIDEiP25092.

PTM databases

iPTMnetiP25092.
PhosphoSitePlusiP25092.

Expressioni

Gene expression databases

BgeeiENSG00000070019.
CleanExiHS_GUCY2C.
HS_STAR.
GenevisibleiP25092. HS.

Organism-specific databases

HPAiHPA037655.

Interactioni

Subunit structurei

Homotrimer. Interacts via its C-terminal region with PDZK2. Interacts with the lectin chaperone VIP36.3 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
PDZD3Q86UT5-24EBI-2816795,EBI-8299496

Protein-protein interaction databases

BioGridi109239. 1 interactor.
IntActiP25092. 3 interactors.
MINTiMINT-261763.
STRINGi9606.ENSP00000261170.

Structurei

3D structure databases

ProteinModelPortaliP25092.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini489 – 749Protein kinasePROSITE-ProRule annotationAdd BLAST261
Domaini824 – 954Guanylate cyclasePROSITE-ProRule annotationAdd BLAST131

Domaini

The protein kinase domain is predicted to be catalytically inactive.

Sequence similaritiesi

Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.PROSITE-ProRule annotation
Contains 1 guanylate cyclase domain.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1023. Eukaryota.
COG2114. LUCA.
GeneTreeiENSGT00760000118959.
HOGENOMiHOG000112833.
HOVERGENiHBG106967.
InParanoidiP25092.
KOiK12320.
OMAiAPDYMKN.
OrthoDBiEOG091G01F8.
PhylomeDBiP25092.

Family and domain databases

Gene3Di3.30.70.1230. 1 hit.
InterProiIPR001054. A/G_cyclase.
IPR018297. A/G_cyclase_CS.
IPR011009. Kinase-like_dom.
IPR029787. Nucleotide_cyclase.
IPR028082. Peripla_BP_I.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF00211. Guanylate_cyc. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SMARTiSM00044. CYCc. 1 hit.
[Graphical view]
SUPFAMiSSF53822. SSF53822. 1 hit.
SSF55073. SSF55073. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00452. GUANYLATE_CYCLASE_1. 1 hit.
PS50125. GUANYLATE_CYCLASE_2. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P25092-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKTLLLDLAL WSLLFQPGWL SFSSQVSQNC HNGSYEISVL MMGNSAFAEP
60 70 80 90 100
LKNLEDAVNE GLEIVRGRLQ NAGLNVTVNA TFMYSDGLIH NSGDCRSSTC
110 120 130 140 150
EGLDLLRKIS NAQRMGCVLI GPSCTYSTFQ MYLDTELSYP MISAGSFGLS
160 170 180 190 200
CDYKETLTRL MSPARKLMYF LVNFWKTNDL PFKTYSWSTS YVYKNGTETE
210 220 230 240 250
DCFWYLNALE ASVSYFSHEL GFKVVLRQDK EFQDILMDHN RKSNVIIMCG
260 270 280 290 300
GPEFLYKLKG DRAVAEDIVI ILVDLFNDQY FEDNVTAPDY MKNVLVLTLS
310 320 330 340 350
PGNSLLNSSF SRNLSPTKRD FALAYLNGIL LFGHMLKIFL ENGENITTPK
360 370 380 390 400
FAHAFRNLTF EGYDGPVTLD DWGDVDSTMV LLYTSVDTKK YKVLLTYDTH
410 420 430 440 450
VNKTYPVDMS PTFTWKNSKL PNDITGRGPQ ILMIAVFTLT GAVVLLLLVA
460 470 480 490 500
LLMLRKYRKD YELRQKKWSH IPPENIFPLE TNETNHVSLK IDDDKRRDTI
510 520 530 540 550
QRLRQCKYDK KRVILKDLKH NDGNFTEKQK IELNKLLQID YYNLTKFYGT
560 570 580 590 600
VKLDTMIFGV IEYCERGSLR EVLNDTISYP DGTFMDWEFK ISVLYDIAKG
610 620 630 640 650
MSYLHSSKTE VHGRLKSTNC VVDSRMVVKI TDFGCNSILP PKKDLWTAPE
660 670 680 690 700
HLRQANISQK GDVYSYGIIA QEIILRKETF YTLSCRDRNE KIFRVENSNG
710 720 730 740 750
MKPFRPDLFL ETAEEKELEV YLLVKNCWEE DPEKRPDFKK IETTLAKIFG
760 770 780 790 800
LFHDQKNESY MDTLIRRLQL YSRNLEHLVE ERTQLYKAER DRADRLNFML
810 820 830 840 850
LPRLVVKSLK EKGFVEPELY EEVTIYFSDI VGFTTICKYS TPMEVVDMLN
860 870 880 890 900
DIYKSFDHIV DHHDVYKVET IGDAYMVASG LPKRNGNRHA IDIAKMALEI
910 920 930 940 950
LSFMGTFELE HLPGLPIWIR IGVHSGPCAA GVVGIKMPRY CLFGDTVNTA
960 970 980 990 1000
SRMESTGLPL RIHVSGSTIA ILKRTECQFL YEVRGETYLK GRGNETTYWL
1010 1020 1030 1040 1050
TGMKDQKFNL PTPPTVENQQ RLQAEFSDMI ANSLQKRQAA GIRSQKPRRV
1060 1070
ASYKKGTLEY LQLNTTDKES TYF
Length:1,073
Mass (Da):123,403
Last modified:November 2, 2010 - v2
Checksum:i486A4DE6F9097E22
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti322A → R in AAB19934 (PubMed:1718270).Curated1
Sequence conflicti331L → V in AAB19934 (PubMed:1718270).Curated1
Sequence conflicti509D → V in AAB19934 (PubMed:1718270).Curated1
Sequence conflicti543N → T in AAB19934 (PubMed:1718270).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04222130C → R.1 PublicationCorresponds to variant rs56142849dbSNPEnsembl.1
Natural variantiVAR_04222261G → R in a metastatic melanoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_042223114R → Q.1 PublicationCorresponds to variant rs56275235dbSNPEnsembl.1
Natural variantiVAR_049253281F → L.5 PublicationsCorresponds to variant rs1420635dbSNPEnsembl.1
Natural variantiVAR_068174387D → G in MECIL; activation of guanylate cyclase activity is 60% lower than in wild-type. 1 PublicationCorresponds to variant rs587776905dbSNPEnsembl.1
Natural variantiVAR_042224464R → L.1 PublicationCorresponds to variant rs55684775dbSNPEnsembl.1
Natural variantiVAR_042225610E → K.1 PublicationCorresponds to variant rs55897626dbSNPEnsembl.1
Natural variantiVAR_067724840S → I in DIAR6; activating mutation; exposure of the mutant receptor to its ligands results in markedly increased production of cyclic guanosine monophosphate. 1 PublicationCorresponds to variant rs587776871dbSNPEnsembl.1
Natural variantiVAR_042226859I → V.1 PublicationCorresponds to variant rs34890806dbSNPEnsembl.1
Natural variantiVAR_0422271045Q → R.1 PublicationCorresponds to variant rs35617837dbSNPEnsembl.1
Natural variantiVAR_0422281072Y → C.1 PublicationCorresponds to variant rs35179392dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS8664.1.
PIRiA40940. OYHUHX.
RefSeqiNP_004954.2. NM_004963.3.
UniGeneiHs.524278.

Genome annotation databases

EnsembliENST00000261170; ENSP00000261170; ENSG00000070019.
GeneIDi2984.
KEGGihsa:2984.
UCSCiuc001rcd.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Web resourcesi

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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.
CCDSiCCDS8664.1.
PIRiA40940. OYHUHX.
RefSeqiNP_004954.2. NM_004963.3.
UniGeneiHs.524278.

3D structure databases

ProteinModelPortaliP25092.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109239. 1 interactor.
IntActiP25092. 3 interactors.
MINTiMINT-261763.
STRINGi9606.ENSP00000261170.

Chemistry databases

ChEMBLiCHEMBL1795197.
DrugBankiDB08890. Linaclotide.
GuidetoPHARMACOLOGYi1750.

Protein family/group databases

TCDBi8.A.85.1.1. the guanylate cyclase (gc) family.

PTM databases

iPTMnetiP25092.
PhosphoSitePlusiP25092.

Polymorphism and mutation databases

BioMutaiGUCY2C.
DMDMi311033390.

Proteomic databases

MaxQBiP25092.
PaxDbiP25092.
PeptideAtlasiP25092.
PRIDEiP25092.

Protocols and materials databases

DNASUi2984.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000261170; ENSP00000261170; ENSG00000070019.
GeneIDi2984.
KEGGihsa:2984.
UCSCiuc001rcd.4. human.

Organism-specific databases

CTDi2984.
DisGeNETi2984.
GeneCardsiGUCY2C.
H-InvDBHIX0036867.
HGNCiHGNC:4688. GUCY2C.
HPAiHPA037655.
MalaCardsiGUCY2C.
MIMi601330. gene.
614616. phenotype.
614665. phenotype.
neXtProtiNX_P25092.
OpenTargetsiENSG00000070019.
Orphaneti314373. Chronic diarrhea due to guanylate cyclase 2C overactivity.
314376. Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency.
PharmGKBiPA29069.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1023. Eukaryota.
COG2114. LUCA.
GeneTreeiENSGT00760000118959.
HOGENOMiHOG000112833.
HOVERGENiHBG106967.
InParanoidiP25092.
KOiK12320.
OMAiAPDYMKN.
OrthoDBiEOG091G01F8.
PhylomeDBiP25092.

Enzyme and pathway databases

BioCyciZFISH:HS00979-MONOMER.
BRENDAi4.6.1.2. 2681.
SIGNORiP25092.

Miscellaneous databases

GeneWikiiGuanylate_cyclase_2C.
GenomeRNAii2984.
PROiP25092.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000070019.
CleanExiHS_GUCY2C.
HS_STAR.
GenevisibleiP25092. HS.

Family and domain databases

Gene3Di3.30.70.1230. 1 hit.
InterProiIPR001054. A/G_cyclase.
IPR018297. A/G_cyclase_CS.
IPR011009. Kinase-like_dom.
IPR029787. Nucleotide_cyclase.
IPR028082. Peripla_BP_I.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF00211. Guanylate_cyc. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SMARTiSM00044. CYCc. 1 hit.
[Graphical view]
SUPFAMiSSF53822. SSF53822. 1 hit.
SSF55073. SSF55073. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS00452. GUANYLATE_CYCLASE_1. 1 hit.
PS50125. GUANYLATE_CYCLASE_2. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGUC2C_HUMAN
AccessioniPrimary (citable) accession number: P25092
Secondary accession number(s): B2RMY6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 1, 1992
Last sequence update: November 2, 2010
Last modified: November 30, 2016
This is version 172 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

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