O43306 · ADCY6_HUMAN
- ProteinAdenylate cyclase type 6
- GeneADCY6
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids1168 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Catalyzes the formation of the signaling molecule cAMP downstream of G protein-coupled receptors (PubMed:17110384, PubMed:17916776).
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).
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).
Catalytic activity
- ATP = 3',5'-cyclic AMP + diphosphate
Cofactor
Mn2+ (UniProtKB | Rhea| CHEBI:29035 )
Note: Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).
Activity regulation
Activated by G(s) G alpha protein GNAS (By similarity).
Inhibited by G(i) G alpha protein GNAI1 (By similarity).
Is further activated by the complex formed by GNB1 and GNG2 (PubMed:17110384).
Activated by forskolin (PubMed:17110384, PubMed:17916776).
Inhibited by calcium ions, already at micromolar concentrations (By similarity).
Inhibited by adenosine, AMP and their analogs (By similarity).
Phosphorylation by RAF1 results in its activation (By similarity).
Inhibited by G(i) G alpha protein GNAI1 (By similarity).
Is further activated by the complex formed by GNB1 and GNG2 (PubMed:17110384).
Activated by forskolin (PubMed:17110384, PubMed:17916776).
Inhibited by calcium ions, already at micromolar concentrations (By similarity).
Inhibited by adenosine, AMP and their analogs (By similarity).
Phosphorylation by RAF1 results in its activation (By similarity).
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 384 | Mg2+ 1 (UniProtKB | ChEBI); catalytic | ||||
Sequence: D | ||||||
Binding site | 384 | Mg2+ 2 (UniProtKB | ChEBI); catalytic | ||||
Sequence: D | ||||||
Binding site | 384-389 | ATP (UniProtKB | ChEBI) | ||||
Sequence: DIEGFT | ||||||
Binding site | 385 | Mg2+ 2 (UniProtKB | ChEBI); catalytic | ||||
Sequence: I | ||||||
Binding site | 426-428 | ATP (UniProtKB | ChEBI) | ||||
Sequence: LGD | ||||||
Binding site | 428 | Mg2+ 1 (UniProtKB | ChEBI); catalytic | ||||
Sequence: D | ||||||
Binding site | 428 | Mg2+ 2 (UniProtKB | ChEBI); catalytic | ||||
Sequence: D | ||||||
Binding site | 472 | ATP (UniProtKB | ChEBI) | ||||
Sequence: R | ||||||
Binding site | 1031 | ATP (UniProtKB | ChEBI) | ||||
Sequence: K | ||||||
Binding site | 1105-1107 | ATP (UniProtKB | ChEBI) | ||||
Sequence: DIW | ||||||
Binding site | 1112-1116 | ATP (UniProtKB | ChEBI) | ||||
Sequence: NVSSR | ||||||
Binding site | 1152 | ATP (UniProtKB | ChEBI) | ||||
Sequence: K |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameAdenylate cyclase type 6
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO43306
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-151 | Cytoplasmic | ||||
Sequence: MSWFSGLLVPKVDERKTAWGERNGQKRSRRRGTRAGGFCTPRYMSCLRDAEPPSPTPAGPPRCPWQDDAFIRRGGPGKGKELGLRAVALGFEDTEVTTTAGGTAEVAPDAVPRSGRSCWRRLVQVFQSKQFRSAKLERLYQRYFFQMNQSS | ||||||
Transmembrane | 152-168 | Helical | ||||
Sequence: LTLLMAVLVLLTAVLLA | ||||||
Transmembrane | 181-197 | Helical | ||||
Sequence: VALLACAAALFVGLMVV | ||||||
Transmembrane | 214-230 | Helical | ||||
Sequence: VVLGILAAVQVGGALAA | ||||||
Transmembrane | 239-255 | Helical | ||||
Sequence: LWCPVFFVYIAYTLLPI | ||||||
Transmembrane | 259-275 | Helical | ||||
Sequence: AAVLSGLGLSTLHLILA | ||||||
Transmembrane | 289-305 | Helical | ||||
Sequence: LGANVLLFLCTNVIGIC | ||||||
Topological domain | 306-673 | Cytoplasmic | ||||
Sequence: THYPAEVSQRQAFQETRGYIQARLHLQHENRQQERLLLSVLPQHVAMEMKEDINTKKEDMMFHKIYIQKHDNVSILFADIEGFTSLASQCTAQELVMTLNELFARFDKLAAENHCLRIKILGDCYYCVSGLPEARADHAHCCVEMGVDMIEAISLVREVTGVNVNMRVGIHSGRVHCGVLGLRKWQFDVWSNDVTLANHMEAGGRAGRIHITRATLQYLNGDYEVEPGRGGERNAYLKEQHIETFLILGASQKRKEEKAMLAKLQRTRANSMEGLMPRWVPDRAFSRTKDSKAFRQMGIDDSSKDNRGTQDALNPEDEVDEFLSRAIDARSIDQLRKDHVRRFLLTFQREDLEKKYSRKVDPRFGAYV | ||||||
Transmembrane | 674-691 | Helical | ||||
Sequence: ACALLVFCFICFIQLLIF | ||||||
Transmembrane | 702-718 | Helical | ||||
Sequence: ASIFLLLLITVLICAVY | ||||||
Transmembrane | 743-759 | Helical | ||||
Sequence: TAVGIFSVLLVFTSAIA | ||||||
Topological domain | 760-819 | Extracellular | ||||
Sequence: NMFTCNHTPIRSCAARMLNLTPADITACHLQQLNYSLGLDAPLCEGTMPTCSFPEYFIGN | ||||||
Transmembrane | 820-836 | Helical | ||||
Sequence: MLLSLLASSVFLHISSI | ||||||
Transmembrane | 839-855 | Helical | ||||
Sequence: LAMIFVLGLIYLVLLLL | ||||||
Transmembrane | 897-913 | Helical | ||||
Sequence: MTPVILLVFALALYLHA | ||||||
Topological domain | 914-1168 | Cytoplasmic | ||||
Sequence: QQVESTARLDFLWKLQATGEKEEMEELQAYNRRLLHNILPKDVAAHFLARERRNDELYYQSCECVAVMFASIANFSEFYVELEANNEGVECLRLLNEIIADFDEIISEERFRQLEKIKTIGSTYMAASGLNASTYDQVGRSHITALADYAMRLMEQMKHINEHSFNNFQMKIGLNMGPVVAGVIGARKPQYDIWGNTVNVSSRMDSTGVPDRIQVTTDLYQVLAAKGYQLECRGVVKVKGKGEMTTYFLNGGPSS |
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Lethal congenital contracture syndrome 8 (LCCS8)
- Note
- 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 alsoMIM:616287
Natural variants in LCCS8
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_073434 | 1116 | R>C | in LCCS8; dbSNP:rs786204798 |
Features
Showing features for natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_048249 | 674 | no effect on basal enzyme activity, but increased enzyme activity upon activation via G-proteins or forskolin; dbSNP:rs3730071 | |||
Sequence: A → S | ||||||
Natural variant | VAR_073434 | 1116 | in LCCS8; dbSNP:rs786204798 | |||
Sequence: R → C |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 1,322 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue, modified residue (large scale data), glycosylation.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000195699 | 1-1168 | UniProt | Adenylate cyclase type 6 | |||
Sequence: MSWFSGLLVPKVDERKTAWGERNGQKRSRRRGTRAGGFCTPRYMSCLRDAEPPSPTPAGPPRCPWQDDAFIRRGGPGKGKELGLRAVALGFEDTEVTTTAGGTAEVAPDAVPRSGRSCWRRLVQVFQSKQFRSAKLERLYQRYFFQMNQSSLTLLMAVLVLLTAVLLAFHAAPARPQPAYVALLACAAALFVGLMVVCNRHSFRQDSMWVVSYVVLGILAAVQVGGALAADPRSPSAGLWCPVFFVYIAYTLLPIRMRAAVLSGLGLSTLHLILAWQLNRGDAFLWKQLGANVLLFLCTNVIGICTHYPAEVSQRQAFQETRGYIQARLHLQHENRQQERLLLSVLPQHVAMEMKEDINTKKEDMMFHKIYIQKHDNVSILFADIEGFTSLASQCTAQELVMTLNELFARFDKLAAENHCLRIKILGDCYYCVSGLPEARADHAHCCVEMGVDMIEAISLVREVTGVNVNMRVGIHSGRVHCGVLGLRKWQFDVWSNDVTLANHMEAGGRAGRIHITRATLQYLNGDYEVEPGRGGERNAYLKEQHIETFLILGASQKRKEEKAMLAKLQRTRANSMEGLMPRWVPDRAFSRTKDSKAFRQMGIDDSSKDNRGTQDALNPEDEVDEFLSRAIDARSIDQLRKDHVRRFLLTFQREDLEKKYSRKVDPRFGAYVACALLVFCFICFIQLLIFPHSTLMLGIYASIFLLLLITVLICAVYSCGSLFPKALQRLSRSIVRSRAHSTAVGIFSVLLVFTSAIANMFTCNHTPIRSCAARMLNLTPADITACHLQQLNYSLGLDAPLCEGTMPTCSFPEYFIGNMLLSLLASSVFLHISSIGKLAMIFVLGLIYLVLLLLGPPATIFDNYDLLLGVHGLASSNETFDGLDCPAAGRVALKYMTPVILLVFALALYLHAQQVESTARLDFLWKLQATGEKEEMEELQAYNRRLLHNILPKDVAAHFLARERRNDELYYQSCECVAVMFASIANFSEFYVELEANNEGVECLRLLNEIIADFDEIISEERFRQLEKIKTIGSTYMAASGLNASTYDQVGRSHITALADYAMRLMEQMKHINEHSFNNFQMKIGLNMGPVVAGVIGARKPQYDIWGNTVNVSSRMDSTGVPDRIQVTTDLYQVLAAKGYQLECRGVVKVKGKGEMTTYFLNGGPSS | |||||||
Modified residue | 54 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 54 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 556 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 576 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 576 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 614 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 662 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Glycosylation | 793 | UniProt | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | |||||||
Modified residue | 919 | UniProt | Phosphothreonine | ||||
Sequence: T |
Post-translational modification
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.
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Structure
Family & Domains
Domain
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.
Sequence similarities
Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
O43306-1
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.
- Name1
- Length1,168
- Mass (Da)130,615
- Last updated2001-01-11 v2
- Checksum127BB6E67F73AA61
O43306-2
- Name2
- Differences from canonical
- 762-814: Missing
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
F8VZJ5 | F8VZJ5_HUMAN | ADCY6 | 82 |
Sequence caution
Features
Showing features for alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_000244 | 762-814 | in isoform 2 | |||
Sequence: Missing |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF250226 EMBL· GenBank· DDBJ | AAF82478.1 EMBL· GenBank· DDBJ | mRNA | ||
AB007882 EMBL· GenBank· DDBJ | BAA24852.2 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
BC064923 EMBL· GenBank· DDBJ | - | mRNA | No translation available. |