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UniProtKB - O43306 (ADCY6_HUMAN)

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Protein

Adenylate cyclase type 6

Gene

ADCY6

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

Functioni

Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors (PubMed:17916776, PubMed:17110384). Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells (PubMed:17916776). Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption. Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion. Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion (By similarity). Signaling mediates cAMP-dependent activation of protein kinase PKA. This promotes increased phosphorylation of various proteins, including AKT. Plays a role in regulating cardiac sarcoplasmic reticulum Ca2+ uptake and storage, and is required for normal heart ventricular contractibility. May contribute to normal heart function (By similarity). Mediates vasodilatation after activation of beta-adrenergic receptors by isoproterenol (PubMed:17916776). Contributes to bone cell responses to mechanical stimuli (By similarity).By similarity2 Publications

Catalytic activityi

ATP = 3',5'-cyclic AMP + diphosphate.2 Publications

Cofactori

Mg2+1 Publication, Mn2+1 PublicationNote: Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).By similarity

Enzyme regulationi

Activated by forskolin (PubMed:17916776, PubMed:17110384). Inhibited by calcium ions, already at micromolar concentrations (By similarity). Inhibited by adenosine, AMP and their analogs (By similarity). Activated by GNAS (PubMed:17110384). Is further activated by the complex formed by GNB1 and GNG2 (PubMed:17110384). Phosphorylation by RAF1 results in its activation (By similarity).By similarity1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi384Magnesium 1; catalyticPROSITE-ProRule annotation1
Metal bindingi384Magnesium 2; catalyticPROSITE-ProRule annotation1
Metal bindingi385Magnesium 2; via carbonyl oxygen; catalyticPROSITE-ProRule annotation1
Metal bindingi428Magnesium 1; catalyticPROSITE-ProRule annotation1
Metal bindingi428Magnesium 2; catalyticPROSITE-ProRule annotation1
Binding sitei472ATPBy similarity1
Binding sitei1031ATPBy similarity1
Binding sitei1152ATPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi384 – 389ATPBy similarity6
Nucleotide bindingi426 – 428ATPBy similarity3
Nucleotide bindingi1105 – 1107ATPBy similarity3
Nucleotide bindingi1112 – 1116ATPBy similarity5

GO - Molecular functioni

  • adenylate cyclase activity Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • guanylate cyclase activity Source: GO_Central
  • metal ion binding Source: UniProtKB-KW
  • protein kinase binding Source: BHF-UCL
  • protein kinase C binding Source: UniProtKB
View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionLyase
Biological processcAMP biosynthesis
LigandATP-binding, Magnesium, Manganese, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-HSA-163359 Glucagon signaling in metabolic regulation
R-HSA-163615 PKA activation
R-HSA-164378 PKA activation in glucagon signalling
R-HSA-170660 Adenylate cyclase activating pathway
R-HSA-170670 Adenylate cyclase inhibitory pathway
R-HSA-381676 Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-400042 Adrenaline,noradrenaline inhibits insulin secretion
R-HSA-418555 G alpha (s) signalling events
R-HSA-418594 G alpha (i) signalling events
R-HSA-418597 G alpha (z) signalling events
R-HSA-432040 Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-5610787 Hedgehog 'off' state
SIGNORiO43306

Names & Taxonomyi

Protein namesi
Recommended name:
Adenylate cyclase type 6 (EC:4.6.1.12 Publications)
Alternative name(s):
ATP pyrophosphate-lyase 6
Adenylate cyclase type VI
Adenylyl cyclase 61 Publication
Ca(2+)-inhibitable adenylyl cyclase
Gene namesi
Name:ADCY6
Synonyms:KIAA0422
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

EuPathDBiHostDB:ENSG00000174233.11
HGNCiHGNC:237 ADCY6
MIMi600294 gene
neXtProtiNX_O43306

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 151CytoplasmicSequence analysisAdd BLAST151
Transmembranei152 – 168HelicalSequence analysisAdd BLAST17
Transmembranei181 – 197HelicalSequence analysisAdd BLAST17
Transmembranei214 – 230HelicalSequence analysisAdd BLAST17
Transmembranei239 – 255HelicalSequence analysisAdd BLAST17
Transmembranei259 – 275HelicalSequence analysisAdd BLAST17
Transmembranei289 – 305HelicalSequence analysisAdd BLAST17
Topological domaini306 – 673CytoplasmicSequence analysisAdd BLAST368
Transmembranei674 – 691HelicalSequence analysisAdd BLAST18
Transmembranei702 – 718HelicalSequence analysisAdd BLAST17
Transmembranei743 – 759HelicalSequence analysisAdd BLAST17
Topological domaini760 – 819ExtracellularSequence analysisAdd BLAST60
Transmembranei820 – 836HelicalSequence analysisAdd BLAST17
Transmembranei839 – 855HelicalSequence analysisAdd BLAST17
Transmembranei897 – 913HelicalSequence analysisAdd BLAST17
Topological domaini914 – 1168CytoplasmicSequence analysisAdd BLAST255

Keywords - Cellular componenti

Cell membrane, Cell projection, Cilium, Membrane

Pathology & Biotechi

Involvement in diseasei

Lethal congenital contracture syndrome 8 (LCCS8)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy and congenital non-progressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS8 is an axoglial form of arthrogryposis multiplex congenita, characterized by congenital distal joint contractures, reduced fetal movements, and severe motor paralysis leading to death early in the neonatal period.
See also OMIM:616287
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0734341116R → C in LCCS8. 1 PublicationCorresponds to variant dbSNP:rs786204798EnsemblClinVar.1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi112
MalaCardsiADCY6
MIMi616287 phenotype
OpenTargetsiENSG00000174233
Orphaneti2680 Hypomyelination neuropathy - arthrogryposis
PharmGKBiPA27

Chemistry databases

ChEMBLiCHEMBL2097167
GuidetoPHARMACOLOGYi1283

Polymorphism and mutation databases

BioMutaiADCY6

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001956991 – 1168Adenylate cyclase type 6Add BLAST1168

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei54PhosphoserineCombined sources1
Modified residuei556PhosphoserineBy similarity1
Modified residuei576PhosphoserineCombined sources1
Modified residuei662PhosphoserineBy similarity1
Glycosylationi793N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei919PhosphothreonineBy similarity1

Post-translational modificationi

Phosphorylation by RAF1 increases enzyme activity. Phosphorylation by PKA at Ser-662 inhibits the GNAS-mediated increase in catalytic activity. Phosphorylation by PKC at Ser-556, Ser-662 and Thr-919 inhibits catalytic activity.By similarity

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiO43306
PaxDbiO43306
PeptideAtlasiO43306
PRIDEiO43306
ProteomicsDBi48880
48881 [O43306-2]

PTM databases

iPTMnetiO43306
PhosphoSitePlusiO43306
SwissPalmiO43306

Expressioni

Tissue specificityi

Detected in peripheral blood mononuclear leukocytes (at protein level) (PubMed:17916776). Detected in thyroid (PubMed:10978539).1 Publication

Gene expression databases

BgeeiENSG00000174233
CleanExiHS_ADCY6
ExpressionAtlasiO43306 baseline and differential
GenevisibleiO43306 HS

Organism-specific databases

HPAiCAB018365

Interactioni

Subunit structurei

Part of a complex containing AKAP5, ADCY5, PDE4C and PKD2 (By similarity). Interacts with RAF1 (PubMed:15385642). Interacts (via cytoplasmic N-terminus) with GNAS, GNB1 and GNG2 (PubMed:17110384).By similarity2 Publications

GO - Molecular functioni

  • protein kinase binding Source: BHF-UCL
  • protein kinase C binding Source: UniProtKB
View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi106625, 24 interactors
IntActiO43306, 7 interactors
MINTiO43306
STRINGi9606.ENSP00000311405

Structurei

3D structure databases

ProteinModelPortaliO43306
SMRiO43306
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domaini

The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain.By similarity

Sequence similaritiesi

Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3619 Eukaryota
COG2114 LUCA
GeneTreeiENSGT00760000119042
HOGENOMiHOG000006941
HOVERGENiHBG050458
InParanoidiO43306
KOiK08046
OMAiHIETFLI
OrthoDBiEOG091G05JR
PhylomeDBiO43306
TreeFamiTF313845

Family and domain databases

Gene3Di3.30.70.1230, 2 hits
InterProiView protein in InterPro
IPR001054 A/G_cyclase
IPR018297 A/G_cyclase_CS
IPR032628 AC_N
IPR030672 Adcy
IPR009398 Adcy_conserved_dom
IPR029787 Nucleotide_cyclase
PfamiView protein in Pfam
PF16214 AC_N, 1 hit
PF06327 DUF1053, 1 hit
PF00211 Guanylate_cyc, 2 hits
PIRSFiPIRSF039050 Ade_cyc, 1 hit
SMARTiView protein in SMART
SM00044 CYCc, 2 hits
SUPFAMiSSF55073 SSF55073, 2 hits
PROSITEiView protein in PROSITE
PS00452 GUANYLATE_CYCLASE_1, 2 hits
PS50125 GUANYLATE_CYCLASE_2, 2 hits

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O43306-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSWFSGLLVP KVDERKTAWG ERNGQKRSRR RGTRAGGFCT PRYMSCLRDA 
        60         70         80         90        100
EPPSPTPAGP PRCPWQDDAF IRRGGPGKGK ELGLRAVALG FEDTEVTTTA 
       110        120        130        140        150
GGTAEVAPDA VPRSGRSCWR RLVQVFQSKQ FRSAKLERLY QRYFFQMNQS 
       160        170        180        190        200
SLTLLMAVLV LLTAVLLAFH AAPARPQPAY VALLACAAAL FVGLMVVCNR 
       210        220        230        240        250
HSFRQDSMWV VSYVVLGILA AVQVGGALAA DPRSPSAGLW CPVFFVYIAY 
       260        270        280        290        300
TLLPIRMRAA VLSGLGLSTL HLILAWQLNR GDAFLWKQLG ANVLLFLCTN 
       310        320        330        340        350
VIGICTHYPA EVSQRQAFQE TRGYIQARLH LQHENRQQER LLLSVLPQHV 
       360        370        380        390        400
AMEMKEDINT KKEDMMFHKI YIQKHDNVSI LFADIEGFTS LASQCTAQEL 
       410        420        430        440        450
VMTLNELFAR FDKLAAENHC LRIKILGDCY YCVSGLPEAR ADHAHCCVEM 
       460        470        480        490        500
GVDMIEAISL VREVTGVNVN MRVGIHSGRV HCGVLGLRKW QFDVWSNDVT 
       510        520        530        540        550
LANHMEAGGR AGRIHITRAT LQYLNGDYEV EPGRGGERNA YLKEQHIETF 
       560        570        580        590        600
LILGASQKRK EEKAMLAKLQ RTRANSMEGL MPRWVPDRAF SRTKDSKAFR 
       610        620        630        640        650
QMGIDDSSKD NRGTQDALNP EDEVDEFLSR AIDARSIDQL RKDHVRRFLL 
       660        670        680        690        700
TFQREDLEKK YSRKVDPRFG AYVACALLVF CFICFIQLLI FPHSTLMLGI 
       710        720        730        740        750
YASIFLLLLI TVLICAVYSC GSLFPKALQR LSRSIVRSRA HSTAVGIFSV 
       760        770        780        790        800
LLVFTSAIAN MFTCNHTPIR SCAARMLNLT PADITACHLQ QLNYSLGLDA 
       810        820        830        840        850
PLCEGTMPTC SFPEYFIGNM LLSLLASSVF LHISSIGKLA MIFVLGLIYL 
       860        870        880        890        900
VLLLLGPPAT IFDNYDLLLG VHGLASSNET FDGLDCPAAG RVALKYMTPV 
       910        920        930        940        950
ILLVFALALY LHAQQVESTA RLDFLWKLQA TGEKEEMEEL QAYNRRLLHN 
       960        970        980        990       1000
ILPKDVAAHF LARERRNDEL YYQSCECVAV MFASIANFSE FYVELEANNE 
      1010       1020       1030       1040       1050
GVECLRLLNE IIADFDEIIS EERFRQLEKI KTIGSTYMAA SGLNASTYDQ 
      1060       1070       1080       1090       1100
VGRSHITALA DYAMRLMEQM KHINEHSFNN FQMKIGLNMG PVVAGVIGAR 
      1110       1120       1130       1140       1150
KPQYDIWGNT VNVSSRMDST GVPDRIQVTT DLYQVLAAKG YQLECRGVVK 
      1160 
VKGKGEMTTY FLNGGPSS
Length:1,168
Mass (Da):130,615
Last modified:January 11, 2001 - v2
Checksum:i127BB6E67F73AA61
GO
Isoform 2 (identifier: O43306-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     762-814: Missing.

Note: No experimental confirmation available.
Show »
Length:1,115
Mass (Da):124,865
Checksum:iD1D26C1E15FAC0B0
GO

Sequence cautioni

The sequence BAA24852 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_048249674A → S No effect on basal enzyme activity, but increased enzyme activity upon activation via G-proteins or forskolin. Corresponds to variant dbSNP:rs3730071Ensembl.1
Natural variantiVAR_0734341116R → C in LCCS8. 1 PublicationCorresponds to variant dbSNP:rs786204798EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_000244762 – 814Missing in isoform 2. 1 PublicationAdd BLAST53

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF250226 mRNA Translation: AAF82478.1
AB007882 mRNA Translation: BAA24852.2 Different initiation.
BC064923 mRNA No translation available.
CCDSiCCDS8767.1 [O43306-1]
RefSeqiNP_056085.1, NM_015270.4 [O43306-1]
XP_006719273.1, XM_006719210.3 [O43306-1]
UniGeneiHs.525401
Hs.694408

Genome annotation databases

EnsembliENST00000307885; ENSP00000311405; ENSG00000174233 [O43306-1]
ENST00000357869; ENSP00000350536; ENSG00000174233 [O43306-2]
ENST00000550422; ENSP00000446730; ENSG00000174233 [O43306-2]
GeneIDi112
KEGGihsa:112
UCSCiuc001rsh.5 human [O43306-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiADCY6_HUMAN
AccessioniPrimary (citable) accession number: O43306
Secondary accession number(s): Q9NR75, Q9UDB0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: January 11, 2001
Last modified: June 20, 2018
This is version 181 of the entry and version 2 of the sequence. See 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. SIMILARITY comments
    Index of protein domains and families

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