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Protein

Adenylate cyclase type 6

Gene

Adcy6

Organism
Mus musculus (Mouse)
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:18071070, PubMed:24363043). Functions in signaling cascades downstream of beta-adrenergic receptors in the heart and in vascular smooth muscle cells (PubMed:18071070). Functions in signaling cascades downstream of the vasopressin receptor in the kidney and has a role in renal water reabsorption (PubMed:20466003, PubMed:20864687). Functions in signaling cascades downstream of PTH1R and plays a role in regulating renal phosphate excretion (PubMed:24854272). Functions in signaling cascades downstream of the VIP and SCT receptors in pancreas and contributes to the regulation of pancreatic amylase and fluid secretion (PubMed:23753526). Signaling mediates cAMP-dependent activation of protein kinase PKA and promotes increased phosphorylation of various proteins, including AKT (PubMed:18071070, PubMed:23753526). Plays a role in regulating cardiac sarcoplasmic reticulum Ca2+ uptake and storage, and is required for normal heart ventricular contractibility (PubMed:18071070). May contribute to normal heart function (PubMed:18071070, PubMed:20359598). Mediates vasodilatation after activation of beta-adrenergic receptors by isoproterenol (By similarity). Contributes to bone cell responses to mechanical stimuli (PubMed:20371630, PubMed:24277577).By similarity10 Publications

Catalytic activityi

ATP = 3',5'-cyclic AMP + diphosphate.7 Publications

Cofactori

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

Enzyme regulationi

Activated by forskolin (PubMed:18071070, PubMed:20466003, PubMed:20864687, PubMed:23753526, PubMed:24363043). Inhibited by calcium ions, already at micromolar concentrations (PubMed:1379717, PubMed:18071070). Inhibited by adenosine, AMP and their analogs (By similarity). Activated by GNAS. Is further activated by the complex formed by GNB1 and GNG2 (By similarity). Phosphorylation by RAF1 results in its activation (By similarity).By similarity6 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi382Magnesium 1; catalyticPROSITE-ProRule annotation1
Metal bindingi382Magnesium 2; catalyticPROSITE-ProRule annotation1
Metal bindingi383Magnesium 2; via carbonyl oxygen; catalyticPROSITE-ProRule annotation1
Metal bindingi426Magnesium 1; catalyticPROSITE-ProRule annotation1
Metal bindingi426Magnesium 2; catalyticPROSITE-ProRule annotation1
Binding sitei470ATPBy similarity1
Binding sitei1028ATPBy similarity1
Binding sitei1149ATPBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi382 – 387ATPBy similarity6
Nucleotide bindingi424 – 426ATPBy similarity3
Nucleotide bindingi1102 – 1104ATPBy similarity3
Nucleotide bindingi1109 – 1113ATPBy similarity5

GO - Molecular functioni

  • adenylate cyclase activity Source: UniProtKB
  • ATP binding Source: UniProtKB-KW
  • calcium- and calmodulin-responsive adenylate cyclase activity Source: MGI
  • metal ion binding Source: UniProtKB-KW
  • protein kinase binding Source: BHF-UCL
  • scaffold protein binding Source: MGI

GO - Biological processi

  • adenylate cyclase-activating G-protein coupled receptor signaling pathway Source: UniProtKB
  • adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway Source: GO_Central
  • cAMP biosynthetic process Source: UniProtKB
  • cAMP-mediated signaling Source: GO_Central
  • cellular response to catecholamine stimulus Source: MGI
  • cellular response to forskolin Source: UniProtKB
  • cellular response to prostaglandin E stimulus Source: MGI
  • cellular response to vasopressin Source: UniProtKB
  • dopamine receptor signaling pathway Source: MGI
  • negative regulation of neuron projection development Source: ParkinsonsUK-UCL
  • negative regulation of urine volume Source: UniProtKB
  • regulation of vasodilation Source: MGI
  • renal water homeostasis Source: UniProtKB
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

BRENDAi4.6.1.1. 3474.

Names & Taxonomyi

Protein namesi
Recommended name:
Adenylate cyclase type 6 (EC:4.6.1.16 Publications)
Alternative name(s):
ATP pyrophosphate-lyase 6
Adenylate cyclase type VI
Adenylyl cyclase 62 Publications
Short name:
AC62 Publications
Ca(2+)-inhibitable adenylyl cyclase
Gene namesi
Name:Adcy6
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:87917. Adcy6.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 149CytoplasmicSequence analysisAdd BLAST149
Transmembranei150 – 166HelicalSequence analysisAdd BLAST17
Transmembranei179 – 195HelicalSequence analysisAdd BLAST17
Transmembranei212 – 228HelicalSequence analysisAdd BLAST17
Transmembranei237 – 253HelicalSequence analysisAdd BLAST17
Transmembranei257 – 273HelicalSequence analysisAdd BLAST17
Transmembranei287 – 303HelicalSequence analysisAdd BLAST17
Topological domaini304 – 670CytoplasmicSequence analysisAdd BLAST367
Transmembranei671 – 688HelicalSequence analysisAdd BLAST18
Transmembranei699 – 715HelicalSequence analysisAdd BLAST17
Transmembranei740 – 756HelicalSequence analysisAdd BLAST17
Topological domaini757 – 816ExtracellularSequence analysisAdd BLAST60
Transmembranei817 – 833HelicalSequence analysisAdd BLAST17
Transmembranei836 – 852HelicalSequence analysisAdd BLAST17
Transmembranei894 – 910HelicalSequence analysisAdd BLAST17
Topological domaini911 – 1165CytoplasmicSequence analysisAdd BLAST255

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cell projection, Cilium, Membrane

Pathology & Biotechi

Disruption phenotypei

Mutant mice are born at the expected Mendelian rate, present no obvious phenotype and are fertile (PubMed:18071070, PubMed:20466003, PubMed:23753526, PubMed:24277577). Their hearts display a decrease in left ventricular pressure, both at the basal level and after activation of beta-adrenergic receptors (PubMed:18071070). Besides, their hearts show defects in sarcoplasmic Ca2+ uptake and storage, and decreased levels of protein phosphorylation (PubMed:18071070). Male mice show increased mortality after transversal aortic constriction (PubMed:20359598). In contrast, female mice do not show increased mortality after transversal aortic constriction, and develop less heart hypertrophy and fibrosis than wild-type (PubMed:20359598). Compared to wild-type, mutant mice drink more and produce greater volumes of urine with decreased osmolarity, but there is no difference in the total quantity of excreted urinary solutes and no difference in blood plasma composition (PubMed:20466003, PubMed:20864687). The impaired urinary water homeostasis is due to retention of AQP2 in intracellular vesicles and decreased AQP2 levels at the cell membrane (PubMed:20466003). Mutant mice display increased urinary inorganic phosphate excretion, but normal plasma phosphate levels (PubMed:24854272). Mutant mice display increased plasma levels of PTH and FGF23, the two principal regulators of urinary phosphate excretion (PubMed:24854272). Mutant mice display no obvious skeleton defects, but display less bone formation after load stress than wild-type (PubMed:24277577). Mutant mice lacking both Adcy6 and Pkd1 survive longer and have less severe polycystic kidney disease than mice lacking only Pkd1 (PubMed:24158982).8 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001957001 – 1165Adenylate cyclase type 6Add BLAST1165

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei53PhosphoserineBy similarity1
Modified residuei85PhosphoserineBy similarity1
Glycosylationi277N-linked (GlcNAc...)Sequence analysis1
Modified residuei553PhosphoserineBy similarity1
Modified residuei573PhosphoserineCombined sources1
Modified residuei659PhosphoserineBy similarity1
Glycosylationi790N-linked (GlcNAc...)Sequence analysis1
Glycosylationi875N-linked (GlcNAc...)Sequence analysis1
Modified residuei916PhosphothreonineBy similarity1

Post-translational modificationi

Phosphorylation by RAF1 increases enzyme activity. Phosphorylation by PKA on Ser-659 inhibits the GNAS-mediated increase in catalytic activity. Phosphorylation by PKC on Ser-553, Ser-659 and Thr-916 inhibits catalytic activity.By similarity

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiQ01341.
PaxDbiQ01341.
PRIDEiQ01341.

PTM databases

iPTMnetiQ01341.
PhosphoSitePlusiQ01341.
SwissPalmiQ01341.

Expressioni

Tissue specificityi

Detected in kidney tubules (PubMed:20466003). Detected in primary bone cells with osteocyte morphology (PubMed:24277577). Detected in heart (at protein level) (PubMed:18071070). Highly expressed in heart (PubMed:1379717, PubMed:18071070). Detected in kidney, pancreas acini and ducts (PubMed:23753526). Weakly detectable in brain, intestine, lung and spleen (PubMed:1379717).5 Publications

Gene expression databases

CleanExiMM_ADCY6.

Interactioni

Subunit structurei

Part of a complex containing AKAP5, ADCY5, PDE4C and PKD2 (PubMed:21670265). Interacts with RAF1. Interacts (via cytoplasmic N-terminus) with GNAS, GNB1 and GNG2 (By similarity).By similarity1 Publication

GO - Molecular functioni

  • protein kinase binding Source: BHF-UCL
  • scaffold protein binding Source: MGI

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000093939.

Structurei

3D structure databases

ProteinModelPortaliQ01341.
SMRiQ01341.
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.
HOGENOMiHOG000006941.
HOVERGENiHBG050458.
InParanoidiQ01341.
KOiK08046.
PhylomeDBiQ01341.

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]

Sequencei

Sequence statusi: Complete.

Q01341-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSWFSGLLVP KVDERKTAWG ERNGQKRPRH ANRASGFCAP RYMSCLKNAE
60 70 80 90 100
PPSPTPAAHT RCPWQDEAFI RRAGPGRGVE LGLRSVALGF DDTEVTTPMG
110 120 130 140 150
TAEVAPDTSP RSGPSCWHRL VQVFQSKQFR SAKLERLYQR YFFQMNQSSL
160 170 180 190 200
TLLMAVLVLL MAVLLTFHAA PAQPQPAYVA LLTCASVLFV VLMVVCNRHS
210 220 230 240 250
FRQDSMWVVS YVVLGILAAV QVGGALAANP HSPSAGLWCP VFFVYITYTL
260 270 280 290 300
LPIRMRAAVL SGLGLSTLHL ILAWQLNSSD PFLWKQLGAN VVLFLCTNAI
310 320 330 340 350
GVCTHYPAEV SQRQAFQETR GYIQARLHLQ HENRQQERLL LSVLPQHVAM
360 370 380 390 400
EMKEDINTKK EDMMFHKIYI QKHDNVSILF ADIEGFTSLA SQCTAQELVM
410 420 430 440 450
TLNELFARFD KLAAENHCLR IKILGDCYYC VSGLPEARAD HAHCCVEMGV
460 470 480 490 500
DMIEAISLVR EVTGVNVNMR VGIHSGRVHC GVLGLRKWQF DVWSNDVTLA
510 520 530 540 550
NHMEAGGGRR IHITRATLQY LNGDYEVEPG RGGERNAYLK EQCIETFLIL
560 570 580 590 600
GASQKRKEEK AMLAKLQRTR ANSMEGLMPR WVPDRAFSRT KDSKAFRQMG
610 620 630 640 650
IDDSSKDNRG AQDALNPEDE VDEFLGRAID ARSIDQLRKD HVRRFLLTFQ
660 670 680 690 700
REDLEKKYSR KVDPRFGAYV ACALLVFCFI CFIQLLVFPY STLILGIYAA
710 720 730 740 750
IFLLLLVTVL ICAVCSCGSF FPKALQRLSR NIVRSRVHST AVGIFSVLLV
760 770 780 790 800
FISAIANMFT CNHTPIRTCA ARMLNLTPAD VTACHLQQLN YSLGLDAPLC
810 820 830 840 850
EGTAPTCSFP EYFVGNVLLS LLASSVFLHI SSIGKLAMTF ILGFTYLVLL
860 870 880 890 900
LLGPPAAIFD NYDLLLGVHG LASSNETFDG LDCPAVGRVA LKYMTPVILL
910 920 930 940 950
VFALALYLHA QQVESTARLD FLWKLQATGE KEEMEELQAY NRRLLHNILP
960 970 980 990 1000
KDVAAHFLAR ERRNDELYYQ SCECVAVMFA SIANFSEFYV ELEANNEGVE
1010 1020 1030 1040 1050
CLRLLNEIIA DFDEIISEER FRQLEKIKTI GSTYMAASGL NASTYDQVGR
1060 1070 1080 1090 1100
SHITALADYA MRLMEQMKHI NEHSFNNFQM KIGLNMGPVV AGVIGARKPQ
1110 1120 1130 1140 1150
YDIWGNTVNV SSRMDSTGVP DRIQVTTDLY QVLAAKGYQL ECRGVVKVKG
1160
KGEMTTYFLN GGPSS
Length:1,165
Mass (Da):130,319
Last modified:April 1, 1993 - v1
Checksum:i24EE1BB45DF1E87E
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti47K → N in AAA37182 (PubMed:1332848).Curated1
Sequence conflicti76G → A in AAA37182 (PubMed:1332848).Curated1
Sequence conflicti508 – 509GR → RAG in AAA37182 (PubMed:1332848).Curated2
Sequence conflicti737V → G in AAA37182 (PubMed:1332848).Curated1
Sequence conflicti881L → Q in AAA37182 (PubMed:1332848).Curated1
Sequence conflicti990V → M in AAA37182 (PubMed:1332848).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M93422 mRNA. Translation: AAA37174.1.
M96653 mRNA. Translation: AAA37182.1.
PIRiA49201.
RefSeqiNP_031431.2. NM_007405.2.
UniGeneiMm.157091.

Genome annotation databases

GeneIDi11512.
KEGGimmu:11512.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M93422 mRNA. Translation: AAA37174.1.
M96653 mRNA. Translation: AAA37182.1.
PIRiA49201.
RefSeqiNP_031431.2. NM_007405.2.
UniGeneiMm.157091.

3D structure databases

ProteinModelPortaliQ01341.
SMRiQ01341.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000093939.

PTM databases

iPTMnetiQ01341.
PhosphoSitePlusiQ01341.
SwissPalmiQ01341.

Proteomic databases

MaxQBiQ01341.
PaxDbiQ01341.
PRIDEiQ01341.

Protocols and materials databases

DNASUi11512.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi11512.
KEGGimmu:11512.

Organism-specific databases

CTDi112.
MGIiMGI:87917. Adcy6.

Phylogenomic databases

eggNOGiKOG3619. Eukaryota.
COG2114. LUCA.
HOGENOMiHOG000006941.
HOVERGENiHBG050458.
InParanoidiQ01341.
KOiK08046.
PhylomeDBiQ01341.

Enzyme and pathway databases

BRENDAi4.6.1.1. 3474.

Miscellaneous databases

ChiTaRSiAdcy6. mouse.
PROiQ01341.
SOURCEiSearch...

Gene expression databases

CleanExiMM_ADCY6.

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_MOUSE
AccessioniPrimary (citable) accession number: Q01341
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: November 2, 2016
This is version 151 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. 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.