ADCY8_HUMAN
ID ADCY8_HUMAN Reviewed; 1251 AA.
AC P40145;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=Adenylate cyclase type 8 {ECO:0000305};
DE EC=4.6.1.1 {ECO:0000250|UniProtKB:P40146};
DE AltName: Full=ATP pyrophosphate-lyase 8;
DE AltName: Full=Adenylate cyclase type VIII {ECO:0000303|PubMed:8076676};
DE AltName: Full=Adenylyl cyclase 8 {ECO:0000303|PubMed:25403481};
DE Short=AC8;
DE AltName: Full=Ca(2+)/calmodulin-activated adenylyl cyclase;
GN Name=ADCY8;
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 [MRNA].
RC TISSUE=Brain stem;
RX PubMed=8076676; DOI=10.1016/0014-5793(94)00836-1;
RA Defer N., Marinx O., Stengel D., Danisova A., Iourgenko V., Matsuoka I.,
RA Caput D., Hanoune J.;
RT "Molecular cloning of the human type VIII adenylyl cyclase.";
RL FEBS Lett. 351:109-113(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 577-1251, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=1715695; DOI=10.1016/0006-291x(91)91392-p;
RA Parma J., Stengel D., Gannage M.H., Poyard M., Barouki R., Hanoune J.;
RT "Sequence of a human brain adenylyl cyclase partial cDNA: evidence for a
RT consensus cyclase specific domain.";
RL Biochem. Biophys. Res. Commun. 179:455-462(1991).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [4]
RP TISSUE SPECIFICITY.
RX PubMed=25403481; DOI=10.1007/s00125-014-3445-z;
RA Raoux M., Vacher P., Papin J., Picard A., Kostrzewa E., Devin A.,
RA Gaitan J., Limon I., Kas M.J., Magnan C., Lang J.;
RT "Multilevel control of glucose homeostasis by adenylyl cyclase 8.";
RL Diabetologia 58:749-757(2015).
RN [5]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-881.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Catalyzes the formation of cAMP in response to calcium entry
CC leadings to cAMP signaling activation that affect processes suche as
CC synaptic plasticity and insulin secretion. Plays a role in many brain
CC functions, such as learning, memory, drug addiction, and anxiety
CC modulation through regulation of synaptic plasticity by modulating
CC long-term memory and long-term potentiation (LTP) through CREB
CC transcription factor activity modulation. Plays a central role in
CC insulin secretion by controlling glucose homeostasis through glucagon-
CC like peptide 1 and glucose signaling pathway and maintains insulin
CC secretion through calcium-dependent PKA activation leading to vesicle
CC pool replenishment. Also, allows PTGER3 to induce potentiation of
CC PTGER4-mediated PLA2 secretion by switching from a negative to a
CC positive regulation, during the IL1B induced-dedifferentiation of
CC smooth muscle cells. {ECO:0000250|UniProtKB:P40146}.
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:0000250|UniProtKB:P40146};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P40146};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:P40146};
CC Note=Binds 2 magnesium ions per subunit. Is also active with manganese
CC (in vitro). {ECO:0000250|UniProtKB:P30803};
CC -!- ACTIVITY REGULATION: At rest, the N- and C-terminal domains interact,
CC as part of a larger autoinhibitory complex, with calmodulin pre-
CC associated at the N-terminal domain. Upon a calcium rise, calmodulin
CC becomes calcium-saturated and subsequently binds to the C-terminal
CC domain. Fully calcium-saturated calmodulin then leaves the N-terminal
CC domain, binding solely to the C-terminal domain, and the whole
CC autoinhibitory complex dissociates, resulting in activation of
CC adenylate cyclase. As local calcium concentrations decrease, the
CC calmodulin becomes calcium free and binds once more to the N-terminal
CC domain, whereupon the whole system returns to rest with the re-
CC association of the autoinhibitory complex. In non-excitable cells,
CC activated by capacitative calcium entry (CCE) through store-operated
CC channels, namely through interaction with ORAI1 and STIM1; membrane
CC raft and caveolae localization and membrane integrity are
CC indispensable. CCE-mediated adenylate cyclase activity is decreased by
CC AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up-
CC regulated by AKAP9 and the mitochondrially targeted AKAP1. In excitable
CC cells, activated during membrane depolarization through L-type voltage-
CC gated calcium channels (VGCC), leading to calcium entry; the L-type
CC alpha subunit is sufficient. Activated via stimulation of the GLP1R.
CC Synergistically activated by calcium/calmodulin and GNAS. Stimulated by
CC forskolin. Inhibited by PKA directly bound to AKAP5 at membrane raft.
CC Inhibition by acute activation of OPRM1 and activation by chronic
CC activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and
CC G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by
CC G beta-gamma dimer. {ECO:0000250|UniProtKB:P40146}.
CC -!- SUBUNIT: Homodimer; via transmembrane domain. Monomer. Heterodimer.
CC Oligemer; via transmembrane domain. Interacts with PRKAR2A and AKAP5;
CC inhibits adenylate cyclase activity through PKA phosphorylation.
CC Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory
CC effects of PKA on adenylate cyclase activity; interaction is dependent
CC of catalytically active PPP2CA; antagonizes interaction with
CC calmodulin. Interacts with AKAP5 (palmitoylated form); promotes the
CC phosphorylation of ADCY8 after store-operated calcium entry (SOCE)
CC stimulation at membrane raft. Interacts with ORAI1; interaction is
CC calcium store depletion independent; interaction occurs in membrane
CC raft; interaction increases markedly after store depletion; positively
CC regulates SOCE-induced adenylate cyclase activity; contributes to the
CC targeting of ADCY8 to discrete regions of the plasma membrane that are
CC shielded from other calcium events. Interacts with STIM1. Interacts
CC with actin; interaction is calcium independent; interaction is affected
CC by calcium-calmodulin; interaction controls the distribution and
CC regulation of ADCY8. Interacts with calmodulin; at rest, interacts via
CC N-terminal domain; upon a calcium rise, calmodulin becomes calcium-
CC saturated and subsequently binds to the C-terminal domain forming an
CC autoinhibitory complex; fully calcium-saturated calmodulin leaves the
CC N-terminal domain, binding solely to the C-terminal domain leading to
CC dissociation of autoinhibitory complex and resulting in activation of
CC adenylate cyclase; antagonizes interaction with PPP2CA; interaction is
CC calcium dependent. Interacts with PPP2R5D.
CC {ECO:0000250|UniProtKB:P40146}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P97490};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:P97490}. Basolateral
CC cell membrane {ECO:0000250|UniProtKB:P97490}. Apical cell membrane
CC {ECO:0000250|UniProtKB:P97490}. Synapse {ECO:0000250|UniProtKB:P97490}.
CC Cell projection, dendrite {ECO:0000250|UniProtKB:P97490}. Cell
CC projection, axon {ECO:0000250|UniProtKB:P97490}. Presynaptic cell
CC membrane {ECO:0000250|UniProtKB:P97490}. Postsynaptic density
CC {ECO:0000250|UniProtKB:P97490}. Membrane raft
CC {ECO:0000250|UniProtKB:P40146}. Membrane, coated pit
CC {ECO:0000250|UniProtKB:P40146}. Cytoplasmic vesicle, clathrin-coated
CC vesicle membrane {ECO:0000250|UniProtKB:P40146}. Membrane, caveola
CC {ECO:0000250|UniProtKB:P40146}. Note=Localized to dendritic arbors (By
CC similarity). Monomeric N-glycosylated species localizes in membrane
CC raft. In contrast, monomeric unglycosylated forms are enriched in
CC clathrin-coated pits and vesicles. Dimers are also localized outside of
CC membrane rafts. Membrane raft localization and integrity is
CC indispensable for CCE-stimulated adenylate cyclase activity (By
CC similarity). {ECO:0000250|UniProtKB:P40146,
CC ECO:0000250|UniProtKB:P97490}.
CC -!- TISSUE SPECIFICITY: Detected in brain cortex (PubMed:1715695).
CC Expressed in islet (PubMed:25403481). {ECO:0000269|PubMed:1715695,
CC ECO:0000269|PubMed:25403481}.
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. The two transmembrane
CC clusters are necessary and suficient for the plasma membrane targeting
CC and oligomers assembly. The N-terminal and C-terminal domains interact
CC at rest as part of a larger autoinhibitory complex, with calmodulin
CC pre-associated at the N-terminal domain; the binding is specifically
CC inhibited by fully calcium-saturated calmodulin, resulting in
CC activation of AC8. {ECO:0000250|UniProtKB:P26769,
CC ECO:0000250|UniProtKB:P40146}.
CC -!- PTM: Phosphorylated by PKA; mediates inhibition of adenylate cyclase
CC activity at membrane raft; does not influence either CALM1 or PPP2CA
CC interaction with ADCY8. {ECO:0000250|UniProtKB:P40146}.
CC -!- PTM: N-glycosylated; N-glycosylation is responsible for raft-targeting;
CC is not necessary for CCE-stimulated adenylate cyclase activity.
CC {ECO:0000250|UniProtKB:P40146}.
CC -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase
CC family. {ECO:0000255|PROSITE-ProRule:PRU00099}.
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DR EMBL; Z35309; CAA84552.1; -; mRNA.
DR EMBL; M83533; AAA35523.2; -; mRNA.
DR CCDS; CCDS6363.1; -.
DR PIR; PQ0227; PQ0227.
DR PIR; S48687; S48687.
DR RefSeq; NP_001106.1; NM_001115.2.
DR AlphaFoldDB; P40145; -.
DR SMR; P40145; -.
DR BioGRID; 106627; 28.
DR IntAct; P40145; 2.
DR STRING; 9606.ENSP00000286355; -.
DR BindingDB; P40145; -.
DR ChEMBL; CHEMBL2960; -.
DR GlyGen; P40145; 3 sites.
DR iPTMnet; P40145; -.
DR PhosphoSitePlus; P40145; -.
DR BioMuta; ADCY8; -.
DR DMDM; 729242; -.
DR MassIVE; P40145; -.
DR PaxDb; P40145; -.
DR PeptideAtlas; P40145; -.
DR PRIDE; P40145; -.
DR ProteomicsDB; 55337; -.
DR Antibodypedia; 4355; 236 antibodies from 30 providers.
DR DNASU; 114; -.
DR Ensembl; ENST00000286355.10; ENSP00000286355.5; ENSG00000155897.10.
DR GeneID; 114; -.
DR KEGG; hsa:114; -.
DR MANE-Select; ENST00000286355.10; ENSP00000286355.5; NM_001115.3; NP_001106.1.
DR UCSC; uc003ytd.5; human.
DR CTD; 114; -.
DR DisGeNET; 114; -.
DR GeneCards; ADCY8; -.
DR HGNC; HGNC:239; ADCY8.
DR HPA; ENSG00000155897; Group enriched (brain, epididymis).
DR MIM; 103070; gene.
DR neXtProt; NX_P40145; -.
DR OpenTargets; ENSG00000155897; -.
DR PharmGKB; PA29; -.
DR VEuPathDB; HostDB:ENSG00000155897; -.
DR eggNOG; KOG3619; Eukaryota.
DR GeneTree; ENSGT00940000158742; -.
DR HOGENOM; CLU_001072_3_0_1; -.
DR InParanoid; P40145; -.
DR OMA; TLNCLND; -.
DR OrthoDB; 107368at2759; -.
DR PhylomeDB; P40145; -.
DR TreeFam; TF313845; -.
DR PathwayCommons; P40145; -.
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-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-442720; CREB1 phosphorylation through the activation of Adenylate Cyclase.
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; P40145; -.
DR SIGNOR; P40145; -.
DR BioGRID-ORCS; 114; 11 hits in 1068 CRISPR screens.
DR ChiTaRS; ADCY8; human.
DR GeneWiki; ADCY8; -.
DR GenomeRNAi; 114; -.
DR Pharos; P40145; Tchem.
DR PRO; PR:P40145; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; P40145; protein.
DR Bgee; ENSG00000155897; Expressed in lateral nuclear group of thalamus and 94 other tissues.
DR ExpressionAtlas; P40145; baseline and differential.
DR Genevisible; P40145; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB.
DR GO; GO:0005901; C:caveola; ISS:UniProtKB.
DR GO; GO:0005905; C:clathrin-coated pit; ISS:UniProtKB.
DR GO; GO:0030665; C:clathrin-coated vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0060076; C:excitatory synapse; ISS:UniProtKB.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0098686; C:hippocampal mossy fiber to CA3 synapse; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR GO; GO:0016020; C:membrane; ISS:UniProtKB.
DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR GO; GO:0032809; C:neuronal cell body membrane; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0044853; C:plasma membrane raft; ISS:UniProtKB.
DR GO; GO:0014069; C:postsynaptic density; ISS:UniProtKB.
DR GO; GO:0048786; C:presynaptic active zone; ISS:UniProtKB.
DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl.
DR GO; GO:0003779; F:actin binding; ISS:UniProtKB.
DR GO; GO:0004016; F:adenylate cyclase activity; IBA:GO_Central.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008294; F:calcium- and calmodulin-responsive adenylate cyclase activity; ISS:UniProtKB.
DR GO; GO:0005516; F:calmodulin binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046983; F:protein dimerization activity; ISS:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISS:UniProtKB.
DR GO; GO:0034199; P:activation of protein kinase A activity; ISS:UniProtKB.
DR GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0006171; P:cAMP biosynthetic process; IBA:GO_Central.
DR GO; GO:0071277; P:cellular response to calcium ion; ISS:UniProtKB.
DR GO; GO:1904322; P:cellular response to forskolin; ISS:UniProtKB.
DR GO; GO:0071377; P:cellular response to glucagon stimulus; ISS:UniProtKB.
DR GO; GO:0071333; P:cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0071315; P:cellular response to morphine; ISS:UniProtKB.
DR GO; GO:0038003; P:G protein-coupled opioid receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0010255; P:glucose mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0007611; P:learning or memory; TAS:ProtInc.
DR GO; GO:0007626; P:locomotory behavior; ISS:UniProtKB.
DR GO; GO:0007616; P:long-term memory; IEA:Ensembl.
DR GO; GO:0007613; P:memory; ISS:UniProtKB.
DR GO; GO:0150076; P:neuroinflammatory response; ISS:UniProtKB.
DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; ISS:UniProtKB.
DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:1900454; P:positive regulation of long-term synaptic depression; ISS:UniProtKB.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; ISS:UniProtKB.
DR GO; GO:0031915; P:positive regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0051259; P:protein complex oligomerization; ISS:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; ISS:UniProtKB.
DR GO; GO:0080135; P:regulation of cellular response to stress; ISS:UniProtKB.
DR GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; ISS:UniProtKB.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR CDD; cd07302; CHD; 2.
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 ATP-binding; cAMP biosynthesis; Cell membrane; Cell projection; Coated pit;
KW Cytoplasmic vesicle; Glycoprotein; Lyase; Magnesium; Manganese; Membrane;
KW Metal-binding; Methylation; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Repeat; Synapse; Transmembrane; Transmembrane helix.
FT CHAIN 1..1251
FT /note="Adenylate cyclase type 8"
FT /id="PRO_0000195705"
FT TOPO_DOM 1..182
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 183..203
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 212..232
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 247..267
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 274..294
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 296..316
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 321..341
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 342..715
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 716..736
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 738..758
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 787..807
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 831..851
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 861..881
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 894..914
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 915..1251
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..182
FT /note="Involved in ORAI1, STIM1, PPP2CA and PPP2R1A
FT interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 1..109
FT /note="Involved in AKAP5 and PRKAR2A interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 50..92
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1109..1251
FT /note="Involved in CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 1200..1215
FT /note="Required for both calcium stimulation and
FT maintenance of autoinhibition"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT REGION 1223..1251
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 38..40
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT MOTIF 49..51
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT COMPBIAS 1223..1241
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 419..424
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 419
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 419
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 420
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 461..463
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 463
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 463
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 507
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P30803"
FT BINDING 1034
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1109..1111
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1116..1120
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT BINDING 1156
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P26769"
FT SITE 1199
FT /note="Essential for autoinhibition maintenance by
FT promoting interaction of the N and C termini"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1200
FT /note="Essential for autoinhibition maintenance"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1203
FT /note="Essential for autoinhibition maintenance by
FT promoting interaction of the N and C termini"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1205
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT SITE 1207
FT /note="Essential for CALM1 interaction"
FT /evidence="ECO:0000250|UniProtKB:P40146"
FT MOD_RES 55
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:P97490"
FT MOD_RES 614
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97490"
FT MOD_RES 624
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97490"
FT CARBOHYD 817
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 821
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 888
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 80
FT /note="A -> T (in dbSNP:rs2228949)"
FT /id="VAR_029188"
FT VARIANT 881
FT /note="F -> L (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036328"
SQ SEQUENCE 1251 AA; 140122 MW; ABF25C40493E07C3 CRC64;
MELSDVRCLT GSEELYTIHP TPPAGDGRSA SRPQRLLWQT AVRHITEQRF IHGHRGGSGS
GSGGSGKASD PAGGGPNHHA PQLSGDSALP LYSLGPGERA HSTCGTKVFP ERSGSGSASG
SGGGGDLGFL HLDCAPSNSD FFLNGGYSYR GVIFPTLRNS FKSRDLERLY QRYFLGQRRK
SEVVMNVLDV LTKLTLLVLH LSLASAPMDP LKGILLGFFT GIEVVICALV VVRKDTTSHT
YLQYSGVVTW VAMTTQILAA GLGYGLLGDG IGYVLFTLFA TYSMLPLPLT WAILAGLGTS
LLQVILQVVI PRLAVISINQ VVAQAVLFMC MNTAGIFISY LSDRAQRQAF LETRRCVEAR
LRLETENQRQ ERLVLSVLPR FVVLEMINDM TNVEDEHLQH QFHRIYIHRY ENVSILFADV
KGFTNLSTTL SAQELVRMLN ELFARFDRLA HEHHCLRIKI LGDCYYCVSG LPEPRQDHAH
CCVEMGLSMI KTIRYVRSRT KHDVDMRIGI HSGSVLCGVL GLRKWQFDVW SWDVDIANKL
ESGGIPGRIH ISKATLDCLN GDYNVEEGHG KERNEFLRKH NIETYLIKQP EDSLLSLPED
IVKESVSSSD RRNSGATFTE GSWSPELPFD NIVGKQNTLA ALTRNSINLL PNHLAQALHV
QSGPEEINKR IEHTIDLRSG DKLRREHIKP FSLMFKDSSL EHKYSQMRDE VFKSNLVCAF
IVLLFITAIQ SLLPSSRVMP MTIQFSILIM LHSALVLITT AEDYKCLPLI LRKTCCWINE
TYLARNVIIF ASILINFLGA ILNILWCDFD KSIPLKNLTF NSSAVFTDIC SYPEYFVFTG
VLAMVTCAVF LRLNSVLKLA VLLIMIAIYA LLTETVYAGL FLRYDNLNHS GEDFLGTKEV
SLLLMAMFLL AVFYHGQQLE YTARLDFLWR VQAKEEINEM KELREHNENM LRNILPSHVA
RHFLEKDRDN EELYSQSYDA VGVMFASIPG FADFYSQTEM NNQGVECLRL LNEIIADFDE
LLGEDRFQDI EKIKTIGSTY MAVSGLSPEK QQCEDKWGHL CALADFSLAL TESIQEINKH
SFNNFELRIG ISHGSVVAGV IGAKKPQYDI WGKTVNLASR MDSTGVSGRI QVPEETYLIL
KDQGFAFDYR GEIYVKGISE QEGKIKTYFL LGRVQPNPFI LPPRRLPGQY SLAAVVLGLV
QSLNRQRQKQ LLNENNNTGI IKGHYNRRTL LSPSGTEPGA QAEGTDKSDL P
