GCYA2_HUMAN
ID GCYA2_HUMAN Reviewed; 732 AA.
AC P33402; A1L4C4; B7ZLT5;
DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1994, sequence version 1.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Guanylate cyclase soluble subunit alpha-2;
DE Short=GCS-alpha-2;
DE EC=4.6.1.2;
GN Name=GUCY1A2; Synonyms=GUC1A2, GUCSA2;
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].
RX PubMed=1683630; DOI=10.1016/0014-5793(91)80871-y;
RA Harteneck C., Wedel B., Koesling D., Malkewitz J., Boehme E., Schultz G.;
RT "Molecular cloning and expression of a new alpha-subunit of soluble
RT guanylyl cyclase. Interchangeability of the alpha-subunits of the enzyme.";
RL FEBS Lett. 292:217-222(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=7673142; DOI=10.1074/jbc.270.36.21109;
RA Behrends S., Harteneck C., Schultz G., Koesling D.;
RT "A variant of the alpha 2 subunit of soluble guanylyl cyclase contains an
RT insert homologous to a region within adenylyl cyclases and functions as a
RT dominant negative protein.";
RL J. Biol. Chem. 270:21109-21113(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
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] (ISOFORMS 1 AND 3).
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 VARIANTS [LARGE SCALE ANALYSIS] VAL-681 AND THR-685.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Has guanylyl cyclase on binding to the beta-1 subunit.
CC -!- FUNCTION: Isoform 2 acts as a negative regulator of guanylyl cyclase
CC activity as it forms non-functional heterodimers with the beta
CC subunits.
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 -!- ACTIVITY REGULATION: Activated by nitric oxide in the presence of
CC magnesium or manganese ions.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta chain.
CC -!- INTERACTION:
CC P33402; Q12959: DLG1; NbExp=2; IntAct=EBI-6911715, EBI-357481;
CC P33402; O15499: GSC2; NbExp=3; IntAct=EBI-6911715, EBI-19954058;
CC P33402; Q14160: SCRIB; NbExp=6; IntAct=EBI-6911715, EBI-357345;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Alpha-2;
CC IsoId=P33402-1; Sequence=Displayed;
CC Name=2; Synonyms=Alpha-2-I;
CC IsoId=P33402-2; Sequence=VSP_001814;
CC Name=3;
CC IsoId=P33402-3; Sequence=VSP_054154;
CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in fetal brain, liver,
CC colon, endothelium and testis. Isoform 2 is expressed only in liver,
CC colon and endothelium.
CC -!- MISCELLANEOUS: There are two types of guanylate cyclases: soluble forms
CC and membrane-associated receptor forms.
CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase
CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}.
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DR EMBL; X63282; CAA44921.1; -; mRNA.
DR EMBL; Z50053; CAA90393.1; -; mRNA.
DR EMBL; AP001282; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP001881; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP003078; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP005014; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471065; EAW67081.1; -; Genomic_DNA.
DR EMBL; BC130484; AAI30485.1; -; mRNA.
DR EMBL; BC130488; AAI30489.1; -; mRNA.
DR EMBL; BC144033; AAI44034.1; -; mRNA.
DR CCDS; CCDS58170.1; -. [P33402-2]
DR CCDS; CCDS8335.1; -. [P33402-1]
DR PIR; S18325; S18325.
DR RefSeq; NP_000846.1; NM_000855.2. [P33402-1]
DR RefSeq; NP_001243353.1; NM_001256424.1. [P33402-2]
DR AlphaFoldDB; P33402; -.
DR SMR; P33402; -.
DR BioGRID; 109232; 14.
DR CORUM; P33402; -.
DR IntAct; P33402; 8.
DR MINT; P33402; -.
DR STRING; 9606.ENSP00000282249; -.
DR ChEMBL; CHEMBL2111348; -.
DR DrugBank; DB09401; Isosorbide.
DR DrugBank; DB01020; Isosorbide mononitrate.
DR DrugBank; DB13749; Magnesium gluconate.
DR DrugBank; DB09241; Methylene blue.
DR DrugBank; DB09282; Molsidomine.
DR DrugBank; DB00435; Nitric Oxide.
DR DrugBank; DB06154; Pentaerythritol tetranitrate.
DR DrugBank; DB13170; Plecanatide.
DR DrugBank; DB08931; Riociguat.
DR DrugCentral; P33402; -.
DR iPTMnet; P33402; -.
DR PhosphoSitePlus; P33402; -.
DR BioMuta; GUCY1A2; -.
DR DMDM; 461897; -.
DR MassIVE; P33402; -.
DR MaxQB; P33402; -.
DR PaxDb; P33402; -.
DR PeptideAtlas; P33402; -.
DR PRIDE; P33402; -.
DR ProteomicsDB; 54910; -. [P33402-1]
DR ProteomicsDB; 54911; -. [P33402-2]
DR Antibodypedia; 4028; 131 antibodies from 18 providers.
DR DNASU; 2977; -.
DR Ensembl; ENST00000282249.6; ENSP00000282249.2; ENSG00000152402.11. [P33402-2]
DR Ensembl; ENST00000347596.2; ENSP00000344874.2; ENSG00000152402.11. [P33402-3]
DR Ensembl; ENST00000526355.7; ENSP00000431245.2; ENSG00000152402.11. [P33402-1]
DR GeneID; 2977; -.
DR KEGG; hsa:2977; -.
DR MANE-Select; ENST00000526355.7; ENSP00000431245.2; NM_000855.3; NP_000846.1.
DR UCSC; uc001pjf.6; human. [P33402-1]
DR CTD; 2977; -.
DR DisGeNET; 2977; -.
DR GeneCards; GUCY1A2; -.
DR HGNC; HGNC:4684; GUCY1A2.
DR HPA; ENSG00000152402; Tissue enhanced (placenta).
DR MIM; 601244; gene.
DR neXtProt; NX_P33402; -.
DR OpenTargets; ENSG00000152402; -.
DR PharmGKB; PA186; -.
DR VEuPathDB; HostDB:ENSG00000152402; -.
DR eggNOG; KOG4171; Eukaryota.
DR GeneTree; ENSGT00940000157765; -.
DR HOGENOM; CLU_011614_5_0_1; -.
DR InParanoid; P33402; -.
DR OMA; SLMLHYF; -.
DR OrthoDB; 531253at2759; -.
DR PhylomeDB; P33402; -.
DR TreeFam; TF351403; -.
DR BRENDA; 4.6.1.2; 2681.
DR PathwayCommons; P33402; -.
DR Reactome; R-HSA-392154; Nitric oxide stimulates guanylate cyclase.
DR Reactome; R-HSA-445355; Smooth Muscle Contraction.
DR SignaLink; P33402; -.
DR SIGNOR; P33402; -.
DR BioGRID-ORCS; 2977; 9 hits in 1068 CRISPR screens.
DR ChiTaRS; GUCY1A2; human.
DR GeneWiki; GUCY1A2; -.
DR GenomeRNAi; 2977; -.
DR Pharos; P33402; Tclin.
DR PRO; PR:P33402; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P33402; protein.
DR Bgee; ENSG00000152402; Expressed in Brodmann (1909) area 23 and 165 other tissues.
DR Genevisible; P33402; HS.
DR GO; GO:0008074; C:guanylate cyclase complex, soluble; IBA:GO_Central.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0004383; F:guanylate cyclase activity; IBA:GO_Central.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0019934; P:cGMP-mediated signaling; IBA:GO_Central.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IEA:Ensembl.
DR GO; GO:0010750; P:positive regulation of nitric oxide mediated signal transduction; IEA:Ensembl.
DR GO; GO:0070482; P:response to oxygen levels; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR CDD; cd07302; CHD; 1.
DR Gene3D; 3.30.450.260; -; 1.
DR Gene3D; 3.30.70.1230; -; 1.
DR Gene3D; 3.90.1520.10; -; 1.
DR InterPro; IPR001054; A/G_cyclase.
DR InterPro; IPR018297; A/G_cyclase_CS.
DR InterPro; IPR038158; H-NOX_domain_sf.
DR InterPro; IPR011644; Heme_NO-bd.
DR InterPro; IPR011645; HNOB_dom_associated.
DR InterPro; IPR042463; HNOB_dom_associated_sf.
DR InterPro; IPR024096; NO_sig/Golgi_transp_ligand-bd.
DR InterPro; IPR029787; Nucleotide_cyclase.
DR Pfam; PF00211; Guanylate_cyc; 1.
DR Pfam; PF07700; HNOB; 1.
DR Pfam; PF07701; HNOBA; 1.
DR SMART; SM00044; CYCc; 1.
DR SUPFAM; SSF111126; SSF111126; 1.
DR SUPFAM; SSF55073; SSF55073; 1.
DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 1.
DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; cGMP biosynthesis; Cytoplasm; GTP-binding; Lyase;
KW Nucleotide-binding; Reference proteome.
FT CHAIN 1..732
FT /note="Guanylate cyclase soluble subunit alpha-2"
FT /id="PRO_0000074113"
FT DOMAIN 521..648
FT /note="Guanylate cyclase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT REGION 1..58
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..19
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 402
FT /note="K -> KSKHVTEGHLTQLSVAGFNSLE (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054154"
FT VAR_SEQ 612
FT /note="Q -> QPQRSELLFSFPVSIQLVPDQHQSETDLGTEK (in isoform
FT 2)"
FT /evidence="ECO:0000303|PubMed:7673142"
FT /id="VSP_001814"
FT VARIANT 681
FT /note="E -> V (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036420"
FT VARIANT 685
FT /note="N -> T (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036421"
SQ SEQUENCE 732 AA; 81750 MW; 79465A7D3FE52DB7 CRC64;
MSRRKISSES FSSLGSDYLE TSPEEEGECP LSRLCWNGSR SPPGPLEPSP AAAAAAAAPA
PTPAASAAAA AATAGARRVQ RRRRVNLDSL GESISRLTAP SPQTIQQTLK RTLQYYEHQV
IGYRDAEKNF HNISNRCSYA DHSNKEEIED VSGILQCTAN ILGLKFEEIQ KRFGEEFFNI
CFHENERVLR AVGGTLQDFF NGFDALLEHI RTSFGKQATL ESPSFLCKEL PEGTLMLHYF
HPHHIVGFAM LGMIKAAGKK IYRLDVEVEQ VANEKLCSDV SNPGNCSCLT FLIKECENTN
IMKNLPQGTS QVPADLRISI NTFCRAFPFH LMFDPSMSVL QLGEGLRKQL RCDTHKVLKF
EDCFEIVSPK VNATFERVLL RLSTPFVIRT KPEASGSENK DKVMEVKGQM IHVPESNSIL
FLGSPCVDKL DELMGRGLHL SDIPIHDATR DVILVGEQAK AQDGLKKRMD KLKATLERTH
QALEEEKKKT VDLLYSIFPG DVAQQLWQGQ QVQARKFDDV TMLFSDIVGF TAICAQCTPM
QVISMLNELY TRFDHQCGFL DIYKVETIGD AYCVAAGLHR KSLCHAKPIA LMALKMMELS
EEVLTPDGRP IQMRIGIHSG SVLAGVVGVR MPRYCLFGNN VTLASKFESG SHPRRINVSP
TTYQLLKREE SFTFIPRSRE ELPDNFPKEI PGICYFLEVR TGPKPPKPSL SSSRIKKVSY
NIGTMFLRET SL
