ID   ADCY3_RAT               Reviewed;        1144 AA.
AC   P21932;
DT   01-MAY-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1991, sequence version 1.
DT   02-SEP-2026, entry version 174.
DE   RecName: Full=Adenylate cyclase type 3;
DE            EC=4.6.1.1 {ECO:0000269|PubMed:1633161, ECO:0000269|PubMed:2255909, ECO:0000269|PubMed:24363043};
DE   AltName: Full=ATP pyrophosphate-lyase 3;
DE   AltName: Full=Adenylate cyclase type III {ECO:0000303|PubMed:2255909};
DE            Short=AC-III;
DE   AltName: Full=Adenylate cyclase, olfactive type;
DE   AltName: Full=Adenylyl cyclase 3;
DE            Short=AC3;
GN   Name=Adcy3 {ECO:0000312|RGD:71009};
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
RP   ACTIVITY REGULATION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RC   TISSUE=Olfactory epithelium;
RX   PubMed=2255909; DOI=10.1126/science.2255909;
RA   Bakalyar H.A., Reed R.R.;
RT   "Identification of a specialized adenylyl cyclase that may mediate odorant
RT   detection.";
RL   Science 250:1403-1406(1990).
RN   [2]
RP   CATALYTIC ACTIVITY, FUNCTION, ACTIVITY REGULATION, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=1633161; DOI=10.1021/bi00143a019;
RA   Choi E.J., Xia Z., Storm D.R.;
RT   "Stimulation of the type III olfactory adenylyl cyclase by calcium and
RT   calmodulin.";
RL   Biochemistry 31:6492-6498(1992).
RN   [3]
RP   SUBCELLULAR LOCATION.
RX   PubMed=15705663; DOI=10.1210/me.2004-0318;
RA   Livera G., Xie F., Garcia M.A., Jaiswal B., Chen J., Law E., Storm D.R.,
RA   Conti M.;
RT   "Inactivation of the mouse adenylyl cyclase 3 gene disrupts male fertility
RT   and spermatozoon function.";
RL   Mol. Endocrinol. 19:1277-1290(2005).
RN   [4]
RP   CATALYTIC ACTIVITY, FUNCTION, AND ACTIVITY REGULATION.
RX   PubMed=24363043; DOI=10.1007/s00210-013-0950-4;
RA   Bogard A.S., Birg A.V., Ostrom R.S.;
RT   "Non-raft adenylyl cyclase 2 defines a cAMP signaling compartment that
RT   selectively regulates IL-6 expression in airway smooth muscle cells:
RT   differential regulation of gene expression by AC isoforms.";
RL   Naunyn Schmiedebergs Arch. Pharmacol. 387:329-339(2014).
RN   [5]
RP   SUMOYLATION, MUTAGENESIS OF LYS-465, SUBCELLULAR LOCATION, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=25908845; DOI=10.1242/jcs.164673;
RA   McIntyre J.C., Joiner A.M., Zhang L., Iniguez-Lluhi J., Martens J.R.;
RT   "SUMOylation regulates ciliary localization of olfactory signaling
RT   proteins.";
RL   J. Cell Sci. 128:1934-1945(2015).
CC   -!- FUNCTION: Catalyzes the formation of the signaling molecule cAMP in
CC       response to G protein signaling (PubMed:1633161, PubMed:2255909,
CC       PubMed:24363043). Participates in signaling cascades triggered by
CC       odorant receptors via its function in cAMP biosynthesis: specifically
CC       activated by G alpha protein GNAL/G(olf) in olfactory epithelium
CC       (PubMed:2255909). Mediates signaling cascades in primary cilia:
CC       specifically activated by G alpha protein GNAS/G(s) in primary cilia.
CC       Plays a role in regulating food intake and body fat accumulation in the
CC       paraventricular nucleus of the hypothalamus (PVH) by acting downstream
CC       of MC4R activation (By similarity). Required for normal sperm motility
CC       and normal male fertility (By similarity).
CC       {ECO:0000250|UniProtKB:O60266, ECO:0000250|UniProtKB:Q8VHH7,
CC       ECO:0000269|PubMed:1633161, ECO:0000269|PubMed:2255909,
CC       ECO:0000269|PubMed:24363043}.
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:0000269|PubMed:1633161, ECO:0000269|PubMed:2255909,
CC         ECO:0000269|PubMed:24363043};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:2255909};
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000250|UniProtKB:P30803};
CC       Note=Binds 2 magnesium ions per subunit. Is also active with manganese
CC       (in vitro). {ECO:0000250|UniProtKB:P30803};
CC   -!- ACTIVITY REGULATION: Specifically activated by the G alpha protein
CC       GNAL/G(olf) in signaling cascades triggered by odorant receptors
CC       (PubMed:2255909). Specifically activated by the G alpha protein
CC       GNAS/G(s) in primary cilia (By similarity). Activated by forskolin
CC       (PubMed:1633161, PubMed:2255909, PubMed:24363043). After forskolin
CC       treatment, activity is further increased by calcium/calmodulin
CC       (PubMed:1633161). In the absence of forskolin, calcium/calmodulin has
CC       little effect on enzyme activity (PubMed:1633161).
CC       {ECO:0000250|UniProtKB:O60266, ECO:0000269|PubMed:1633161,
CC       ECO:0000269|PubMed:2255909, ECO:0000269|PubMed:24363043}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15705663,
CC       ECO:0000269|PubMed:1633161}; Multi-pass membrane protein {ECO:0000255}.
CC       Cell projection, cilium membrane {ECO:0000269|PubMed:2255909,
CC       ECO:0000269|PubMed:25908845}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:O60266}. Cytoplasm
CC       {ECO:0000250|UniProtKB:O60266}. Golgi apparatus
CC       {ECO:0000269|PubMed:15705663}.
CC   -!- TISSUE SPECIFICITY: Detected on cilia on the olfactory epithelium (at
CC       protein level) (PubMed:2255909, PubMed:25908845). Detected on cilia on
CC       the olfactory epithelium. {ECO:0000269|PubMed:2255909}.
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 modules have no catalytic activity, but when they are
CC       brought together, enzyme activity is restored. The active site is at
CC       the interface of the two modules. {ECO:0000250|UniProtKB:P30803}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:2255909}.
CC   -!- PTM: Sumoylated. Sumoylation is required for targeting to olfactory
CC       cilia. {ECO:0000269|PubMed:25908845}.
CC   -!- PTM: Rapidly phosphorylated after stimulation by odorants or forskolin.
CC       Phosphorylation by CaMK2 at Ser-1076 down-regulates enzyme activity.
CC       {ECO:0000250|UniProtKB:Q8VHH7}.
CC   -!- SIMILARITY: Belongs to the adenylyl cyclase class-4/guanylyl cyclase
CC       family. {ECO:0000255|PROSITE-ProRule:PRU00099}.
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DR   EMBL; M55075; AAA40677.1; -; mRNA.
DR   PIR; A39833; A39833.
DR   RefSeq; NP_570135.2; NM_130779.2.
DR   AlphaFoldDB; P21932; -.
DR   SMR; P21932; -.
DR   BioGRID; 249093; 1.
DR   CORUM; P21932; -.
DR   FunCoup; P21932; 3472.
DR   STRING; 10116.ENSRNOP00000005389; -.
DR   BindingDB; P21932; -.
DR   ChEMBL; CHEMBL2095179; -.
DR   DrugCentral; P21932; -.
DR   GlyCosmos; P21932; 1 site, No reported glycans.
DR   GlyGen; P21932; 1 site.
DR   PhosphoSitePlus; P21932; -.
DR   PaxDb; 10116-ENSRNOP00000005389; -.
DR   GeneID; 64508; -.
DR   KEGG; rno:64508; -.
DR   AGR; RGD:71009; -.
DR   CTD; 109; -.
DR   RGD; 71009; Adcy3.
DR   eggNOG; KOG3619; Eukaryota.
DR   InParanoid; P21932; -.
DR   OrthoDB; 10261550at2759; -.
DR   PhylomeDB; P21932; -.
DR   BRENDA; 4.6.1.1; 5301.
DR   Reactome; R-RNO-163615; PKA activation.
DR   Reactome; R-RNO-170660; Adenylate cyclase activating pathway.
DR   Reactome; R-RNO-170670; Adenylate cyclase inhibitory pathway.
DR   Reactome; R-RNO-418597; G alpha (z) signalling events.
DR   Reactome; R-RNO-5610787; Hedgehog 'off' state.
DR   PRO; PR:P21932; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0001669; C:acrosomal vesicle; IDA:RGD.
DR   GO; GO:0090651; C:apical cytoplasm; IDA:RGD.
DR   GO; GO:0060170; C:ciliary membrane; ISO:RGD.
DR   GO; GO:0097538; C:ciliary necklace; IDA:RGD.
DR   GO; GO:0005929; C:cilium; IDA:RGD.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; IDA:RGD.
DR   GO; GO:0098788; C:dendritic knob; IDA:RGD.
DR   GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR   GO; GO:0016020; C:membrane; IDA:RGD.
DR   GO; GO:0043025; C:neuronal cell body; IDA:RGD.
DR   GO; GO:0098804; C:non-motile cilium membrane; ISS:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IDA:RGD.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD.
DR   GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR   GO; GO:0097225; C:sperm midpiece; IDA:RGD.
DR   GO; GO:0004016; F:adenylate cyclase activity; IDA:UniProtKB.
DR   GO; GO:0008294; F:calcium- and calmodulin-responsive adenylate cyclase activity; IDA:RGD.
DR   GO; GO:0007340; P:acrosome reaction; ISS:UniProtKB.
DR   GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR   GO; GO:0006171; P:cAMP biosynthetic process; IDA:UniProtKB.
DR   GO; GO:1904322; P:cellular response to forskolin; IDA:UniProtKB.
DR   GO; GO:0030317; P:flagellated sperm motility; ISS:UniProtKB.
DR   GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR   GO; GO:0032099; P:negative regulation of appetite; ISS:UniProtKB.
DR   GO; GO:0008355; P:olfactory learning; ISS:UniProtKB.
DR   GO; GO:0007608; P:sensory perception of smell; ISO:RGD.
DR   GO; GO:0007338; P:single fertilization; ISS:UniProtKB.
DR   CDD; cd07302; CHD; 2.
DR   FunFam; 3.30.70.1230:FF:000006; Adenylate cyclase; 1.
DR   FunFam; 3.30.70.1230:FF:000009; Adenylate cyclase; 1.
DR   Gene3D; 3.30.70.1230; Nucleotide cyclase; 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; IPR029787; Nucleotide_cyclase.
DR   PANTHER; PTHR45627; ADENYLATE CYCLASE TYPE 1; 1.
DR   PANTHER; PTHR45627:SF30; ADENYLATE CYCLASE TYPE 3; 1.
DR   Pfam; PF16214; AC_N; 1.
DR   Pfam; PF00211; Guanylate_cyc; 2.
DR   PIRSF; PIRSF039050; Ade_cyc; 1.
DR   SMART; SM00044; CYCc; 2.
DR   SUPFAM; SSF55073; Nucleotide cyclase; 2.
DR   PROSITE; PS00452; GUANYLATE_CYCLASE_1; 2.
DR   PROSITE; PS50125; GUANYLATE_CYCLASE_2; 2.
PE   1: Evidence at protein level;
KW   ATP-binding; Calmodulin-binding; cAMP biosynthesis; Cell membrane;
KW   Cell projection; Cytoplasm; Glycoprotein; Golgi apparatus; Isopeptide bond;
KW   Lyase; Magnesium; Manganese; Membrane; Metal-binding; Nucleotide-binding;
KW   Olfaction; Phosphoprotein; Reference proteome; Repeat;
KW   Sensory transduction; Transmembrane; Transmembrane helix; Ubl conjugation.
FT   CHAIN           1..1144
FT                   /note="Adenylate cyclase type 3"
FT                   /id="PRO_0000195689"
FT   TOPO_DOM        1..79
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        80..100
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        105..125
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        139..159
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        173..193
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        226..246
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        381..401
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        402..630
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        631..651
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        662..682
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        706..726
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        755..775
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        777..797
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        833..853
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        854..1144
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REGION          504..563
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        534..543
FT                   /note="Low complexity"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         324..329
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P30803"
FT   BINDING         324
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         324
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         325
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         366..368
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P30803"
FT   BINDING         368
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         368
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         412
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P30803"
FT   BINDING         975
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P26769"
FT   BINDING         1062..1064
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P26769"
FT   BINDING         1069..1073
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P26769"
FT   BINDING         1109
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P26769"
FT   MOD_RES         523
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:O60266"
FT   MOD_RES         578
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHH7"
FT   MOD_RES         1076
FT                   /note="Phosphoserine; by CaMK2"
FT                   /evidence="ECO:0000250|UniProtKB:Q8VHH7"
FT   CARBOHYD        734
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CROSSLNK        465
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO3)"
FT                   /evidence="ECO:0000269|PubMed:25908845"
FT   MUTAGEN         465
FT                   /note="K->R: Abolishes sumoylation. Abolishes location at
FT                   cilia in the olfactory epithelium."
FT                   /evidence="ECO:0000269|PubMed:25908845"
SQ   SEQUENCE   1144 AA;  128936 MW;  21098D028DDBAB55 CRC64;
     MTEDQGFSDP EYSAEYSAEY SVSLPSDPDR GVGRTHEISV RNSGSCLCLP RFMRLTFVPE
     SLENLYQTYF KRQRHETLLV LVVFAALFDC YVVVMCAVVF SSDKLAPLMV AGVGLVLDII
     LFVLCKKGLL PDRVSRKVVP YLLWLLITAQ IFSYLGLNFS RAHAASDTVG WQAFFVFSFF
     ITLPLSLSPI VIISVVSCVV HTLVLGVTVA QQQQDELEGM QLLREILANV FLYLCAIIVG
     IMSYYMADRK HRKAFLEARQ SLEVKMNLEE QSQQQENLML SILPKHVADE MLKDMKKDES
     QKDQQQFNTM YMYRHENVSI LFADIVGFTQ LSSACSAQEL VKLLNELFAR FDKLAAKYHQ
     LRIKILGDCY YCICGLPDYR EDHAVCSILM GLAMVEAISY VREKTKTGVD MRVGVHTGTV
     LGGVLGQKRW QYDVWSTDVT VANKMEAGGI PGRVHISQST MDCLKGEFDV EPGDGGSRCD
     YLDEKGIETY LIIASKPEVK KTAQNGLNGS ALPNGAPASK PSSPALIETK EPNGSAHASG
     STSEEAEEQE AQADNPSFPN PRRRLRLQDL ADRVVDASED EHELNQLLNE ALLERESAQV
     VKKRNTFLLT MRFMDPEMET RYSVEKEKQS GAAFSCSCVV LFCTAMVEIL IDPWLMTNYV
     TFVVGEVLLL ILTICSMAAI FPRAFPKKLV AFSSWIDRTR WARNTWAMLA IFILVMANVV
     DMLSCLQYYM GPYNVTTGIE LDGGCMENPK YYNYVAVLSL IATIMLVQVS HMVKLTLMLL
     VTGAVTAINL YAWCPVFDEY DHKRFQEKDS PMVALEKMQV LSTPGLNGTD SRLPLVPSKY
     SMTVMMFVMM LSFYYFSRHV EKLARTLFLW KIEVHDQKER VYEMRRWNEA LVTNMLPEHV
     ARHFLGSKKR DEELYSQSYD EIGVMFASLP NFADFYTEES INNGGIECLR FLNEIISDFD
     SLLDNPKFRV ITKIKTIGST YMAASGVTPD VNTNGFTSSS KEEKSDKERW QHLADLADFA
     LAMKDTLTNI NNQSFNNFML RIGMNKGGVL AGVIGARKPH YDIWGNTVNV ASRMESTGVM
     GNIQVVEETQ VILREYGFRF VRRGPIFVKG KGELLTFFLK GRDRPAAFPN GSSVTLPHQV
     VDNP
//