ADCY5_HUMAN
ID ADCY5_HUMAN Reviewed; 1261 AA.
AC O95622; B7Z8A6; Q7RTV7; Q8NFM3;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2006, sequence version 3.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Adenylate cyclase type 5;
DE EC=4.6.1.1 {ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:24700542, ECO:0000269|PubMed:26206488};
DE AltName: Full=ATP pyrophosphate-lyase 5;
DE AltName: Full=Adenylate cyclase type V;
DE AltName: Full=Adenylyl cyclase 5;
DE Short=AC5 {ECO:0000303|PubMed:26206488};
GN Name=ADCY5;
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 [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 368-1261 (ISOFORM 1).
RC TISSUE=Heart;
RX PubMed=12503609; DOI=10.1081/rrs-120014589;
RA Ludwig M.G., Seuwen K.;
RT "Characterization of the human adenylyl cyclase gene family: cDNA, gene
RT structure, and tissue distribution of the nine isoforms.";
RL J. Recept. Signal Transduct. 22:79-110(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 560-664 (ISOFORM 1).
RC TISSUE=Heart muscle;
RX PubMed=10481931; DOI=10.1016/s0009-8981(99)00067-4;
RA Raimundo S., Giray J., Volff J.-N., Schwab M., Altenbuchner J., Ratge D.,
RA Wisser H.;
RT "Cloning and sequence of partial cDNAs encoding the human type V and VI
RT adenylyl cyclases and subsequent RNA-quantification in various tissues.";
RL Clin. Chim. Acta 285:155-161(1999).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, SUBCELLULAR LOCATION,
RP PHOSPHORYLATION BY RAF1, INTERACTION WITH RAF1, AND ACTIVITY REGULATION.
RX PubMed=15385642; DOI=10.1124/mol.66.4.921;
RA Ding Q., Gros R., Gray I.D., Taussig R., Ferguson S.S., Feldman R.D.;
RT "Raf kinase activation of adenylyl cyclases: isoform-selective
RT regulation.";
RL Mol. Pharmacol. 66:921-928(2004).
RN [6]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=24740569; DOI=10.2337/db13-1607;
RA Hodson D.J., Mitchell R.K., Marselli L., Pullen T.J., Gimeno Brias S.,
RA Semplici F., Everett K.L., Cooper D.M., Bugliani M., Marchetti P.,
RA Lavallard V., Bosco D., Piemonti L., Johnson P.R., Hughes S.J., Li D.,
RA Li W.H., Shapiro A.M., Rutter G.A.;
RT "ADCY5 couples glucose to insulin secretion in human islets.";
RL Diabetes 63:3009-3021(2014).
RN [7]
RP INTERACTION WITH GNAS; GNB1 AND GNG2, FUNCTION, CATALYTIC ACTIVITY,
RP ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=26206488; DOI=10.1124/mol.115.099556;
RA Brand C.S., Sadana R., Malik S., Smrcka A.V., Dessauer C.W.;
RT "Adenylyl cyclase 5 regulation by Gbetagamma involves isoform specific use
RT of multiple interaction sites.";
RL Mol. Pharmacol. 88:758-767(2015).
RN [8]
RP VARIANT DSKOD THR-726.
RX PubMed=22782511; DOI=10.1001/archneurol.2012.54;
RA Chen Y.Z., Matsushita M.M., Robertson P., Rieder M., Girirajan S.,
RA Antonacci F., Lipe H., Eichler E.E., Nickerson D.A., Bird T.D.,
RA Raskind W.H.;
RT "Autosomal dominant familial dyskinesia and facial myokymia: single exome
RT sequencing identifies a mutation in adenylyl cyclase 5.";
RL Arch. Neurol. 69:630-635(2012).
RN [9]
RP VARIANT DSKOD TRP-418, CHARACTERIZATION OF VARIANTS DSKOD TRP-418 AND
RP THR-726, FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=24700542; DOI=10.1002/ana.24119;
RA Chen Y.Z., Friedman J.R., Chen D.H., Chan G.C., Bloss C.S., Hisama F.M.,
RA Topol S.E., Carson A.R., Pham P.H., Bonkowski E.S., Scott E.R., Lee J.K.,
RA Zhang G., Oliveira G., Xu J., Scott-Van Zeeland A.A., Chen Q., Levy S.,
RA Topol E.J., Storm D., Swanson P.D., Bird T.D., Schork N.J., Raskind W.H.,
RA Torkamani A.;
RT "Gain-of-function ADCY5 mutations in familial dyskinesia with facial
RT myokymia.";
RL Ann. Neurol. 75:542-549(2014).
RN [10]
RP VARIANTS LEU-10 AND VAL-706, VARIANT DSKOD TRP-418, AND TISSUE SPECIFICITY.
RX PubMed=26085604; DOI=10.1212/wnl.0000000000001720;
RA Mencacci N.E., Erro R., Wiethoff S., Hersheson J., Ryten M., Balint B.,
RA Ganos C., Stamelou M., Quinn N., Houlden H., Wood N.W., Bhatia K.P.;
RT "ADCY5 mutations are another cause of benign hereditary chorea.";
RL Neurology 85:80-88(2015).
RN [11]
RP VARIANT DSKOR CYS-1013, AND INVOLVEMENT IN DSKOR.
RX PubMed=28971144; DOI=10.1212/nxg.0000000000000193;
RA Barrett M.J., Williams E.S., Chambers C., Dhamija R.;
RT "Autosomal recessive inheritance of ADCY5-related generalized dystonia and
RT myoclonus.";
RL Neurol. Genet. 3:193-193(2017).
RN [12]
RP VARIANT DSKOR ASN-588, AND INVOLVEMENT IN DSKOR.
RX PubMed=30975617; DOI=10.1016/j.parkreldis.2019.02.039;
RA Bohlega S.A., Abou-Al-Shaar H., Al-Dakheel A., Alajlan H., Bohlega B.S.,
RA Meyer B.F., Monies D., Cupler E.J., Al-Saif A.M.;
RT "Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the
RT genetic spectrum of ADCY5-Related movement disorders.";
RL Parkinsonism Relat. Disord. 64:145-149(2019).
RN [13]
RP VARIANT DSKOR TRP-1238.
RX PubMed=33704598; DOI=10.1007/s10072-021-05152-y;
RA Okamoto N., Miya F., Kitai Y., Tsunoda T., Kato M., Saitoh S., Kanemura Y.,
RA Kosaki K.;
RT "Homozygous ADCY5 mutation causes early-onset movement disorder with severe
RT intellectual disability.";
RL Neurol. Sci. 42:2975-2978(2021).
RN [14]
RP INVOLVEMENT IN NEDHYD.
RX PubMed=34631954; DOI=10.1002/mdc3.13310;
RA Kaiyrzhanov R., Zaki M.S., Maroofian R., Dominik N., Rad A., Vona B.,
RA Houlden H.;
RT "A Novel Homozygous ADCY5 Variant is Associated with a Neurodevelopmental
RT Disorder and Movement Abnormalities.";
RL Mov. Disord. Clin. Pract. 8:1140-1143(2021).
CC -!- FUNCTION: Catalyzes the formation of the signaling molecule cAMP in
CC response to G-protein signaling (PubMed:15385642, PubMed:26206488,
CC PubMed:24700542). Mediates signaling downstream of ADRB1
CC (PubMed:24700542). Regulates the increase of free cytosolic Ca(2+) in
CC response to increased blood glucose levels and contributes to the
CC regulation of Ca(2+)-dependent insulin secretion (PubMed:24740569).
CC {ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:24700542,
CC ECO:0000269|PubMed:24740569, ECO:0000269|PubMed:26206488}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP = 3',5'-cyclic AMP + diphosphate; Xref=Rhea:RHEA:15389,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:58165; EC=4.6.1.1;
CC Evidence={ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:24700542,
CC ECO:0000269|PubMed:26206488};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:15385642};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:15385642};
CC Note=Binds 2 magnesium ions per subunit. Is also active with manganese
CC (in vitro). {ECO:0000250|UniProtKB:P30803};
CC -!- ACTIVITY REGULATION: Activated by forskolin (PubMed:24700542).
CC Activated by GNAS. Activity is further increased by interaction with
CC the G-protein beta and gamma subunit complex formed by GNB1 and GNG2
CC (PubMed:26206488). Is not activated by calmodulin. Inhibited by
CC adenosine and ATP analogs. Inhibited by calcium ions, already at
CC micromolar concentrations (By similarity). Phosphorylation by RAF1
CC results in its activation (PubMed:15385642).
CC {ECO:0000250|UniProtKB:P30803, ECO:0000269|PubMed:15385642,
CC ECO:0000269|PubMed:26206488}.
CC -!- SUBUNIT: Interacts with GNAS, GNB1 and GNG2 (PubMed:26206488). Part of
CC a complex containing AKAP5, ADCY6, PDE4C and PKD2 (By similarity).
CC Interacts with RAF1 (PubMed:15385642). {ECO:0000250|UniProtKB:P84309,
CC ECO:0000269|PubMed:15385642, ECO:0000269|PubMed:26206488}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305|PubMed:15385642,
CC ECO:0000305|PubMed:26206488}; Multi-pass membrane protein. Cell
CC projection, cilium {ECO:0000250|UniProtKB:P84309}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O95622-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O95622-2; Sequence=VSP_042914, VSP_042915;
CC -!- TISSUE SPECIFICITY: Detected in pancreas islets (at protein level).
CC Expressed in the brain, with high expression in the corpus striatum
CC (PubMed:26085604). {ECO:0000269|PubMed:24740569,
CC ECO:0000269|PubMed:26085604}.
CC -!- DOMAIN: The protein contains two modules with six transmembrane helices
CC each; both are required for catalytic activity. Isolated N-terminal or
CC C-terminal guanylate cyclase domains have no catalytic activity, but
CC when they are brought together, enzyme activity is restored. The active
CC site is at the interface of the two domains. Both contribute substrate-
CC binding residues, but the catalytic metal ions are bound exclusively
CC via the N-terminal guanylate cyclase domain.
CC {ECO:0000250|UniProtKB:P30803}.
CC -!- PTM: Phosphorylated by RAF1. {ECO:0000269|PubMed:15385642}.
CC -!- DISEASE: Dyskinesia with orofacial involvement, autosomal recessive
CC (DSKOR) [MIM:619647]: An autosomal recessive disorder characterized by
CC abnormal involuntary movements mainly affecting the limbs and causing
CC walking difficulties, oro-facial dyskinesia, and speech delay. Some
CC patients develop neuropsychiatric features. Cardiomyopathy has rarely
CC been described and may be a manifestation of the disorder.
CC {ECO:0000269|PubMed:28971144, ECO:0000269|PubMed:30975617,
CC ECO:0000269|PubMed:33704598}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Neurodevelopmental disorder with hyperkinetic movements and
CC dyskinesia (NEDHYD) [MIM:619651]: An autosomal recessive disorder
CC characterized by severe global developmental delay, axial hypotonia,
CC impaired intellectual development, poor overall growth, and abnormal
CC involuntary hyperkinetic movements. {ECO:0000269|PubMed:34631954}.
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}.
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DR EMBL; AK303070; BAH13892.1; -; mRNA.
DR EMBL; AC025571; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC112503; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF497517; AAM94374.1; -; mRNA.
DR EMBL; U65473; AAD00121.1; -; mRNA.
DR EMBL; BK000371; DAA00057.1; -; mRNA.
DR CCDS; CCDS3022.1; -. [O95622-1]
DR CCDS; CCDS56274.1; -. [O95622-2]
DR RefSeq; NP_001186571.1; NM_001199642.1. [O95622-2]
DR RefSeq; NP_899200.1; NM_183357.2. [O95622-1]
DR AlphaFoldDB; O95622; -.
DR SMR; O95622; -.
DR BioGRID; 106624; 16.
DR IntAct; O95622; 2.
DR STRING; 9606.ENSP00000419361; -.
DR BindingDB; O95622; -.
DR ChEMBL; CHEMBL3189; -.
DR DrugBank; DB06843; 2',5'-DIDEOXY-ADENOSINE 3'-MONOPHOSPHATE.
DR DrugBank; DB09121; Aurothioglucose.
DR DrugBank; DB02587; Colforsin.
DR GuidetoPHARMACOLOGY; 1282; -.
DR GlyGen; O95622; 2 sites.
DR iPTMnet; O95622; -.
DR PhosphoSitePlus; O95622; -.
DR BioMuta; ADCY5; -.
DR EPD; O95622; -.
DR jPOST; O95622; -.
DR MassIVE; O95622; -.
DR MaxQB; O95622; -.
DR PaxDb; O95622; -.
DR PeptideAtlas; O95622; -.
DR PRIDE; O95622; -.
DR ProteomicsDB; 50954; -. [O95622-1]
DR ProteomicsDB; 50955; -. [O95622-2]
DR Antibodypedia; 2807; 162 antibodies from 28 providers.
DR DNASU; 111; -.
DR Ensembl; ENST00000309879.9; ENSP00000308685.5; ENSG00000173175.15. [O95622-2]
DR Ensembl; ENST00000462833.6; ENSP00000419361.1; ENSG00000173175.15. [O95622-1]
DR GeneID; 111; -.
DR KEGG; hsa:111; -.
DR MANE-Select; ENST00000462833.6; ENSP00000419361.1; NM_183357.3; NP_899200.1.
DR UCSC; uc003egh.3; human. [O95622-1]
DR CTD; 111; -.
DR DisGeNET; 111; -.
DR GeneCards; ADCY5; -.
DR GeneReviews; ADCY5; -.
DR HGNC; HGNC:236; ADCY5.
DR HPA; ENSG00000173175; Tissue enhanced (brain, heart muscle).
DR MalaCards; ADCY5; -.
DR MIM; 600293; gene.
DR MIM; 606703; phenotype.
DR MIM; 619647; phenotype.
DR MIM; 619651; phenotype.
DR neXtProt; NX_O95622; -.
DR OpenTargets; ENSG00000173175; -.
DR Orphanet; 1429; Benign hereditary chorea.
DR Orphanet; 324588; Familial dyskinesia and facial myokymia.
DR PharmGKB; PA24563; -.
DR VEuPathDB; HostDB:ENSG00000173175; -.
DR eggNOG; KOG3619; Eukaryota.
DR GeneTree; ENSGT00940000158054; -.
DR HOGENOM; CLU_001072_2_0_1; -.
DR InParanoid; O95622; -.
DR OMA; KVGRTHI; -.
DR OrthoDB; 215180at2759; -.
DR PhylomeDB; O95622; -.
DR TreeFam; TF313845; -.
DR BRENDA; 4.6.1.1; 2681.
DR PathwayCommons; O95622; -.
DR Reactome; R-HSA-163359; Glucagon signaling in metabolic regulation.
DR Reactome; R-HSA-163615; PKA activation.
DR Reactome; R-HSA-164378; PKA activation in glucagon signalling.
DR Reactome; R-HSA-170660; Adenylate cyclase activating pathway.
DR Reactome; R-HSA-170670; Adenylate cyclase inhibitory pathway.
DR Reactome; R-HSA-381676; Glucagon-like Peptide-1 (GLP1) regulates insulin secretion.
DR Reactome; R-HSA-400042; Adrenaline,noradrenaline inhibits insulin secretion.
DR Reactome; R-HSA-418555; G alpha (s) signalling events.
DR Reactome; R-HSA-418594; G alpha (i) signalling events.
DR Reactome; R-HSA-418597; G alpha (z) signalling events.
DR Reactome; R-HSA-432040; Vasopressin regulates renal water homeostasis via Aquaporins.
DR Reactome; R-HSA-5610787; Hedgehog 'off' state.
DR Reactome; R-HSA-9634597; GPER1 signaling.
DR Reactome; R-HSA-9660821; ADORA2B mediated anti-inflammatory cytokines production.
DR Reactome; R-HSA-9664323; FCGR3A-mediated IL10 synthesis.
DR SignaLink; O95622; -.
DR SIGNOR; O95622; -.
DR BioGRID-ORCS; 111; 12 hits in 1069 CRISPR screens.
DR ChiTaRS; ADCY5; human.
DR GeneWiki; ADCY5; -.
DR GenomeRNAi; 111; -.
DR Pharos; O95622; Tchem.
DR PRO; PR:O95622; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; O95622; protein.
DR Bgee; ENSG00000173175; Expressed in apex of heart and 125 other tissues.
DR ExpressionAtlas; O95622; baseline and differential.
DR Genevisible; O95622; HS.
DR GO; GO:0005929; C:cilium; ISS:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0045111; C:intermediate filament cytoskeleton; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; ISS:BHF-UCL.
DR GO; GO:0004016; F:adenylate cyclase activity; IDA:UniProtKB.
DR GO; GO:0008179; F:adenylate cyclase binding; ISS:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0097110; F:scaffold protein binding; IEA:Ensembl.
DR GO; GO:0007191; P:adenylate cyclase-activating dopamine receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0007195; P:adenylate cyclase-inhibiting dopamine receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0006171; P:cAMP biosynthetic process; IDA:UniProtKB.
DR GO; GO:1904322; P:cellular response to forskolin; IDA:UniProtKB.
DR GO; GO:0001973; P:G protein-coupled adenosine receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl.
DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IMP:UniProtKB.
DR GO; GO:0061178; P:regulation of insulin secretion involved in cellular response to glucose stimulus; IMP:UniProtKB.
DR CDD; cd07302; CHD; 1.
DR Gene3D; 3.30.70.1230; -; 2.
DR InterPro; IPR001054; A/G_cyclase.
DR InterPro; IPR018297; A/G_cyclase_CS.
DR InterPro; IPR032628; AC_N.
DR InterPro; IPR030672; Adcy.
DR InterPro; IPR009398; Adcy_conserved_dom.
DR InterPro; IPR029787; Nucleotide_cyclase.
DR Pfam; PF16214; AC_N; 1.
DR Pfam; PF06327; DUF1053; 1.
DR Pfam; PF00211; Guanylate_cyc; 2.
DR PIRSF; PIRSF039050; Ade_cyc; 1.
DR SMART; SM00044; CYCc; 2.
DR SUPFAM; SSF55073; SSF55073; 2.
DR PROSITE; PS00452; GUANYLATE_CYCLASE_1; 2.
DR PROSITE; PS50125; GUANYLATE_CYCLASE_2; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; ATP-binding; cAMP biosynthesis; Cell membrane;
KW Cell projection; Cilium; Disease variant; Glycoprotein;
KW Intellectual disability; Lyase; Magnesium; Membrane; Metal-binding;
KW Methylation; Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Repeat; Transmembrane; Transmembrane helix.
FT CHAIN 1..1261
FT /note="Adenylate cyclase type 5"
FT /id="PRO_0000195694"
FT TOPO_DOM 1..195
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 196..216
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 242..262
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 268..288
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 299..319
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 325..345
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 374..394
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 395..769
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 770..790
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 792..812
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 836..856
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 857..909
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 910..930
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 935..955
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 984..1004
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1005..1261
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 469..596
FT /note="Guanylate cyclase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT DOMAIN 1071..1210
FT /note="Guanylate cyclase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT REGION 1..195
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 103..117
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 155..175
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 474..479
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 474
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 474
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 475
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 516..518
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 518
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="1"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 518
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_label="2"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00099"
FT BINDING 562
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 1123
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1197..1199
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1204..1208
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1244
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT MOD_RES 23
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P84309"
FT MOD_RES 96
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P84309"
FT MOD_RES 155
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P84309"
FT MOD_RES 666
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O43306"
FT MOD_RES 754
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q03343"
FT MOD_RES 1011
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q03343"
FT CARBOHYD 870
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 887
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..28
FT /note="MSGSKSVSPPGYAAQKTAAPAPRGGPEH -> MKSQKEGCCSRGDLSIQTGP
FT GGEWAPRR (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042914"
FT VAR_SEQ 29..378
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_042915"
FT VARIANT 10
FT /note="P -> L"
FT /evidence="ECO:0000269|PubMed:26085604"
FT /id="VAR_086538"
FT VARIANT 418
FT /note="R -> W (in DSKOD; increases cAMP production upon
FT activation of ADRB1; dbSNP:rs864309483)"
FT /evidence="ECO:0000269|PubMed:24700542,
FT ECO:0000269|PubMed:26085604"
FT /id="VAR_073778"
FT VARIANT 588
FT /note="D -> N (in DSKOR)"
FT /evidence="ECO:0000269|PubMed:30975617"
FT /id="VAR_086539"
FT VARIANT 706
FT /note="A -> V"
FT /evidence="ECO:0000269|PubMed:26085604"
FT /id="VAR_086540"
FT VARIANT 726
FT /note="A -> T (in DSKOD; increases cAMP production upon
FT activation of ADRB1; dbSNP:rs796065306)"
FT /evidence="ECO:0000269|PubMed:22782511,
FT ECO:0000269|PubMed:24700542"
FT /id="VAR_068821"
FT VARIANT 1013
FT /note="R -> C (in DSKOR)"
FT /evidence="ECO:0000269|PubMed:28971144"
FT /id="VAR_086541"
FT VARIANT 1238
FT /note="R -> W (in DSKOR)"
FT /evidence="ECO:0000269|PubMed:33704598"
FT /id="VAR_086542"
SQ SEQUENCE 1261 AA; 138908 MW; C50492A0B053694F CRC64;
MSGSKSVSPP GYAAQKTAAP APRGGPEHRS AWGEADSRAN GYPHAPGGSA RGSTKKPGGA
VTPQQQQRLA SRWRSDDDDD PPLSGDDPLA GGFGFSFRSK SAWQERGGDD CGRGSRRQRR
GAASGGSTRA PPAGGGGGSA AAAASAGGTE VRPRSVEVGL EERRGKGRAA DELEAGAVEG
GEGSGDGGSS ADSGSGAGPG AVLSLGACCL ALLQIFRSKK FPSDKLERLY QRYFFRLNQS
SLTMLMAVLV LVCLVMLAFH AARPPLQLPY LAVLAAAVGV ILIMAVLCNR AAFHQDHMGL
ACYALIAVVL AVQVVGLLLP QPRSASEGIW WTVFFIYTIY TLLPVRMRAA VLSGVLLSAL
HLAIALRTNA QDQFLLKQLV SNVLIFSCTN IVGVCTHYPA EVSQRQAFQE TRECIQARLH
SQRENQQQER LLLSVLPRHV AMEMKADINA KQEDMMFHKI YIQKHDNVSI LFADIEGFTS
LASQCTAQEL VMTLNELFAR FDKLAAENHC LRIKILGDCY YCVSGLPEAR ADHAHCCVEM
GMDMIEAISL VREVTGVNVN MRVGIHSGRV HCGVLGLRKW QFDVWSNDVT LANHMEAGGK
AGRIHITKAT LNYLNGDYEV EPGCGGERNA YLKEHSIETF LILRCTQKRK EEKAMIAKMN
RQRTNSIGHN PPHWGAERPF YNHLGGNQVS KEMKRMGFED PKDKNAQESA NPEDEVDEFL
GRAIDARSID RLRSEHVRKF LLTFREPDLE KKYSKQVDDR FGAYVACASL VFLFICFVQI
TIVPHSIFML SFYLTCSLLL TLVVFVSVIY SCVKLFPSPL QTLSRKIVRS KMNSTLVGVF
TITLVFLAAF VNMFTCNSRD LLGCLAQEHN ISASQVNACH VAESAVNYSL GDEQGFCGSP
WPNCNFPEYF TYSVLLSLLA CSVFLQISCI GKLVLMLAIE LIYVLIVEVP GVTLFDNADL
LVTANAIDFF NNGTSQCPEH ATKVALKVVT PIIISVFVLA LYLHAQQVES TARLDFLWKL
QATEEKEEME ELQAYNRRLL HNILPKDVAA HFLARERRND ELYYQSCECV AVMFASIANF
SEFYVELEAN NEGVECLRLL NEIIADFDEI ISEDRFRQLE KIKTIGSTYM AASGLNDSTY
DKVGKTHIKA LADFAMKLMD QMKYINEHSF NNFQMKIGLN IGPVVAGVIG ARKPQYDIWG
NTVNVASRMD STGVPDRIQV TTDMYQVLAA NTYQLECRGV VKVKGKGEMM TYFLNGGPPL
S
