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Protein

Adenylate cyclase type 6

Gene

ADCY6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi384 – 3841Magnesium 1; catalyticPROSITE-ProRule annotation
Metal bindingi384 – 3841Magnesium 2; catalyticPROSITE-ProRule annotation
Metal bindingi385 – 3851Magnesium 2; via carbonyl oxygen; catalyticPROSITE-ProRule annotation
Metal bindingi428 – 4281Magnesium 1; catalyticPROSITE-ProRule annotation
Metal bindingi428 – 4281Magnesium 2; catalyticPROSITE-ProRule annotation
Binding sitei472 – 4721ATPBy similarity
Binding sitei1031 – 10311ATPBy similarity
Binding sitei1152 – 11521ATPBy similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi384 – 3896ATPBy similarity
Nucleotide bindingi426 – 4283ATPBy similarity
Nucleotide bindingi1105 – 11073ATPBy similarity
Nucleotide bindingi1112 – 11165ATPBy similarity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Lyase

Keywords - Biological processi

cAMP biosynthesis

Keywords - Ligandi

ATP-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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:237. ADCY6.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 151151CytoplasmicSequence analysisAdd
BLAST
Transmembranei152 – 16817HelicalSequence analysisAdd
BLAST
Transmembranei181 – 19717HelicalSequence analysisAdd
BLAST
Transmembranei214 – 23017HelicalSequence analysisAdd
BLAST
Transmembranei239 – 25517HelicalSequence analysisAdd
BLAST
Transmembranei259 – 27517HelicalSequence analysisAdd
BLAST
Transmembranei289 – 30517HelicalSequence analysisAdd
BLAST
Topological domaini306 – 673368CytoplasmicSequence analysisAdd
BLAST
Transmembranei674 – 69118HelicalSequence analysisAdd
BLAST
Transmembranei702 – 71817HelicalSequence analysisAdd
BLAST
Transmembranei743 – 75917HelicalSequence analysisAdd
BLAST
Topological domaini760 – 81960ExtracellularSequence analysisAdd
BLAST
Transmembranei820 – 83617HelicalSequence analysisAdd
BLAST
Transmembranei839 – 85517HelicalSequence analysisAdd
BLAST
Transmembranei897 – 91317HelicalSequence analysisAdd
BLAST
Topological domaini914 – 1168255CytoplasmicSequence analysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

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)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti1116 – 11161R → C in LCCS8. 1 Publication
Corresponds to variant rs786204798 [ dbSNP | Ensembl ].
VAR_073434

Keywords - Diseasei

Disease mutation

Organism-specific databases

MalaCardsiADCY6.
MIMi616287. phenotype.
Orphaneti2680. Hypomyelination neuropathy - arthrogryposis.
PharmGKBiPA27.

Chemistry

ChEMBLiCHEMBL2097167.
GuidetoPHARMACOLOGYi1283.

Polymorphism and mutation databases

BioMutaiADCY6.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 11681168Adenylate cyclase type 6PRO_0000195699Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei54 – 541PhosphoserineCombined sources
Modified residuei556 – 5561PhosphoserineBy similarity
Modified residuei576 – 5761PhosphoserineCombined sources
Modified residuei662 – 6621PhosphoserineBy similarity
Glycosylationi793 – 7931N-linked (GlcNAc...)Sequence analysis
Modified residuei919 – 9191PhosphothreonineBy similarity

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.

PTM databases

iPTMnetiO43306.
PhosphoSiteiO43306.
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-protein interaction databases

BioGridi106625. 18 interactions.
IntActiO43306. 6 interactions.
MINTiMINT-2856766.
STRINGi9606.ENSP00000311405.

Structurei

3D structure databases

ProteinModelPortaliO43306.
SMRiO43306. Positions 364-553.
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
Contains 2 guanylate cyclase domains.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

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

Family and domain databases

Gene3Di3.30.70.1230. 2 hits.
InterProiIPR001054. A/G_cyclase.
IPR018297. A/G_cyclase_CS.
IPR032628. AC_N.
IPR030672. Adcy.
IPR009398. Adcy_conserved_dom.
IPR029787. Nucleotide_cyclase.
[Graphical view]
PfamiPF16214. AC_N. 1 hit.
PF06327. DUF1053. 1 hit.
PF00211. Guanylate_cyc. 2 hits.
[Graphical view]
PIRSFiPIRSF039050. Ade_cyc. 1 hit.
SMARTiSM00044. CYCc. 2 hits.
[Graphical view]
SUPFAMiSSF55073. SSF55073. 2 hits.
PROSITEiPS00452. GUANYLATE_CYCLASE_1. 2 hits.
PS50125. GUANYLATE_CYCLASE_2. 2 hits.
[Graphical view]

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)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti674 – 6741A → S No effect on basal enzyme activity, but increased enzyme activity upon activation via G-proteins or forskolin.
Corresponds to variant rs3730071 [ dbSNP | Ensembl ].
VAR_048249
Natural varianti1116 – 11161R → C in LCCS8. 1 Publication
Corresponds to variant rs786204798 [ dbSNP | Ensembl ].
VAR_073434

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei762 – 81453Missing in isoform 2. 1 PublicationVSP_000244Add
BLAST

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

Cross-referencesi

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.

3D structure databases

ProteinModelPortaliO43306.
SMRiO43306. Positions 364-553.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi106625. 18 interactions.
IntActiO43306. 6 interactions.
MINTiMINT-2856766.
STRINGi9606.ENSP00000311405.

Chemistry

ChEMBLiCHEMBL2097167.
GuidetoPHARMACOLOGYi1283.

PTM databases

iPTMnetiO43306.
PhosphoSiteiO43306.
SwissPalmiO43306.

Polymorphism and mutation databases

BioMutaiADCY6.

Proteomic databases

MaxQBiO43306.
PaxDbiO43306.
PeptideAtlasiO43306.
PRIDEiO43306.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

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]

Organism-specific databases

CTDi112.
GeneCardsiADCY6.
HGNCiHGNC:237. ADCY6.
HPAiCAB018365.
MalaCardsiADCY6.
MIMi600294. gene.
616287. phenotype.
neXtProtiNX_O43306.
Orphaneti2680. Hypomyelination neuropathy - arthrogryposis.
PharmGKBiPA27.
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

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

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.

Miscellaneous databases

GeneWikiiADCY6.
GenomeRNAii112.
PROiO43306.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000174233.
CleanExiHS_ADCY6.
ExpressionAtlasiO43306. baseline and differential.
GenevisibleiO43306. HS.

Family and domain databases

Gene3Di3.30.70.1230. 2 hits.
InterProiIPR001054. A/G_cyclase.
IPR018297. A/G_cyclase_CS.
IPR032628. AC_N.
IPR030672. Adcy.
IPR009398. Adcy_conserved_dom.
IPR029787. Nucleotide_cyclase.
[Graphical view]
PfamiPF16214. AC_N. 1 hit.
PF06327. DUF1053. 1 hit.
PF00211. Guanylate_cyc. 2 hits.
[Graphical view]
PIRSFiPIRSF039050. Ade_cyc. 1 hit.
SMARTiSM00044. CYCc. 2 hits.
[Graphical view]
SUPFAMiSSF55073. SSF55073. 2 hits.
PROSITEiPS00452. GUANYLATE_CYCLASE_1. 2 hits.
PS50125. GUANYLATE_CYCLASE_2. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiADCY6_HUMAN
AccessioniPrimary (citable) accession number: O43306
Secondary accession number(s): Q9NR75, Q9UDB0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: January 11, 2001
Last modified: September 7, 2016
This is version 164 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. 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.