ID   PDE2A_BOVIN             Reviewed;         921 AA.
AC   P14099; Q28064;
DT   01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-1992, sequence version 2.
DT   27-MAR-2024, entry version 150.
DE   RecName: Full=cGMP-dependent 3',5'-cyclic phosphodiesterase {ECO:0000305|PubMed:1654333};
DE            EC=3.1.4.17 {ECO:0000269|PubMed:1654333};
DE   AltName: Full=Cyclic GMP-stimulated phosphodiesterase {ECO:0000303|PubMed:1654333};
DE            Short=CGS-PDE {ECO:0000303|PubMed:1654333};
DE            Short=cGSPDE {ECO:0000303|PubMed:1654333};
GN   Name=PDE2A {ECO:0000250|UniProtKB:O00408};
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE2A1), FUNCTION, CATALYTIC ACTIVITY,
RP   COFACTOR, AND ACTIVITY REGULATION.
RX   PubMed=1654333; DOI=10.1016/s0021-9258(19)47421-8;
RA   Sonnenburg W.K., Mullaney P.J., Beavo J.A.;
RT   "Molecular cloning of a cyclic GMP-stimulated cyclic nucleotide
RT   phosphodiesterase cDNA. Identification and distribution of isozyme
RT   variants.";
RL   J. Biol. Chem. 266:17655-17661(1991).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE2A3).
RC   TISSUE=Brain;
RA   Juilfs D.M., Sonnenburg W.K., Seraji S., Beavo J.A.;
RL   Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 592-921, AND ACETYLATION AT MET-1.
RC   TISSUE=Heart;
RX   PubMed=2176866; DOI=10.1021/bi00496a018;
RA   le Trong H., Beier N., Sonnenburg W.K., Stroop S.D., Walsh K.A.,
RA   Beavo J.A., Charbonneau H.;
RT   "Amino acid sequence of the cyclic GMP stimulated cyclic nucleotide
RT   phosphodiesterase from bovine heart.";
RL   Biochemistry 29:10280-10288(1990).
RN   [4]
RP   PROTEIN SEQUENCE OF 613-694 AND 808-868.
RC   TISSUE=Heart;
RX   PubMed=3025833; DOI=10.1073/pnas.83.24.9308;
RA   Charbonneau H., Beier N., Walsh K.A., Beavo J.A.;
RT   "Identification of a conserved domain among cyclic nucleotide
RT   phosphodiesterases from diverse species.";
RL   Proc. Natl. Acad. Sci. U.S.A. 83:9308-9312(1986).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX   PubMed=6276403; DOI=10.1016/s0021-9258(19)68134-2;
RA   Martins T.J., Mumby M.C., Beavo J.A.;
RT   "Purification and characterization of a cyclic GMP-stimulated cyclic
RT   nucleotide phosphodiesterase from bovine tissues.";
RL   J. Biol. Chem. 257:1973-1979(1982).
CC   -!- FUNCTION: cGMP-activated cyclic nucleotide phosphodiesterase with a
CC       dual-specificity for the second messengers cAMP and cGMP, which are key
CC       regulators of many important physiological processes (PubMed:1654333,
CC       PubMed:6276403). Has a higher efficiency with cGMP compared to cAMP (By
CC       similarity). Plays a role in cell growth and migration (By similarity).
CC       {ECO:0000250|UniProtKB:O00408, ECO:0000269|PubMed:1654333,
CC       ECO:0000269|PubMed:6276403}.
CC   -!- FUNCTION: [Isoform PDE2A2]: Regulates mitochondrial cAMP levels and
CC       respiration. Involved in the regulation of mitochondria
CC       morphology/dynamics and apoptotic cell death via local modulation of
CC       cAMP/PKA signaling in the mitochondrion, including the monitoring of
CC       local cAMP levels at the outer mitochondrial membrane and of PKA-
CC       dependent phosphorylation of DNM1L. {ECO:0000250|UniProtKB:Q01062}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a nucleoside 3',5'-cyclic phosphate + H2O = a nucleoside 5'-
CC         phosphate + H(+); Xref=Rhea:RHEA:14653, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:57867, ChEBI:CHEBI:58464; EC=3.1.4.17;
CC         Evidence={ECO:0000269|PubMed:1654333, ECO:0000269|PubMed:6276403};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14654;
CC         Evidence={ECO:0000305|PubMed:1654333};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746,
CC         ChEBI:CHEBI:58115; Evidence={ECO:0000269|PubMed:1654333,
CC         ECO:0000269|PubMed:6276403};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958;
CC         Evidence={ECO:0000305|PubMed:1654333};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165,
CC         ChEBI:CHEBI:456215; Evidence={ECO:0000269|PubMed:1654333,
CC         ECO:0000269|PubMed:6276403};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25278;
CC         Evidence={ECO:0000305|PubMed:1654333};
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC         Evidence={ECO:0000269|PubMed:1654333};
CC       Note=Binds 2 divalent metal cations per subunit. Site 1 may
CC       preferentially bind zinc ions. {ECO:0000250|UniProtKB:O00408};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:O00408};
CC       Note=Binds 2 divalent metal cations per subunit. Site 2 has a
CC       preference for magnesium ions. {ECO:0000250|UniProtKB:O00408};
CC   -!- ACTIVITY REGULATION: The 3',5'-cyclic-AMP phosphodiesterase activity is
CC       stimulated by 3',5'-cyclic GMP. {ECO:0000269|PubMed:1654333,
CC       ECO:0000269|PubMed:6276403}.
CC   -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:O00408}.
CC   -!- SUBCELLULAR LOCATION: [Isoform PDE2A3]: Cell membrane
CC       {ECO:0000250|UniProtKB:Q01062}; Peripheral membrane protein
CC       {ECO:0000305}.
CC   -!- SUBCELLULAR LOCATION: [Isoform PDE2A1]: Cytoplasm
CC       {ECO:0000250|UniProtKB:Q01062}.
CC   -!- SUBCELLULAR LOCATION: [Isoform PDE2A2]: Mitochondrion
CC       {ECO:0000250|UniProtKB:Q01062}. Mitochondrion inner membrane
CC       {ECO:0000250|UniProtKB:Q01062}. Mitochondrion outer membrane
CC       {ECO:0000250|UniProtKB:Q01062}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC         Comment=Additional isoforms seem to exist.;
CC       Name=PDE2A1;
CC         IsoId=P14099-1; Sequence=Displayed;
CC       Name=PDE2A2;
CC         IsoId=P14099-3; Sequence=Not described;
CC       Name=PDE2A3;
CC         IsoId=P14099-2; Sequence=VSP_004555;
CC   -!- DOMAIN: The GAF 1 domain functions as a dimerization domain.
CC       {ECO:0000250|UniProtKB:Q922S4}.
CC   -!- DOMAIN: The GAF 2 domains binds cGMP, which acts as an allosteric
CC       activator. {ECO:0000250|UniProtKB:Q922S4}.
CC   -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC       PDE2 subfamily. {ECO:0000305}.
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DR   EMBL; M73512; AAA74559.1; -; mRNA.
DR   EMBL; L49503; AAA87353.1; -; mRNA.
DR   PIR; A40981; A40981.
DR   RefSeq; NP_001137318.1; NM_001143846.1.
DR   RefSeq; NP_001243202.1; NM_001256273.1. [P14099-1]
DR   PDB; 3JAB; EM; 11.00 A; B/N=367-551.
DR   PDB; 3JBQ; EM; 11.00 A; C/G=367-551.
DR   PDBsum; 3JAB; -.
DR   PDBsum; 3JBQ; -.
DR   AlphaFoldDB; P14099; -.
DR   SMR; P14099; -.
DR   STRING; 9913.ENSBTAP00000061440; -.
DR   BindingDB; P14099; -.
DR   ChEMBL; CHEMBL3477; -.
DR   DrugCentral; P14099; -.
DR   iPTMnet; P14099; -.
DR   PaxDb; 9913-ENSBTAP00000011077; -.
DR   GeneID; 281971; -.
DR   KEGG; bta:281971; -.
DR   CTD; 5138; -.
DR   eggNOG; KOG3689; Eukaryota.
DR   InParanoid; P14099; -.
DR   Proteomes; UP000009136; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR   GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR   GO; GO:0005759; C:mitochondrial matrix; IBA:GO_Central.
DR   GO; GO:0005741; C:mitochondrial outer membrane; IBA:GO_Central.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR   GO; GO:0042734; C:presynaptic membrane; ISS:UniProtKB.
DR   GO; GO:0097060; C:synaptic membrane; IBA:GO_Central.
DR   GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IDA:UniProtKB.
DR   GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:UniProtKB.
DR   GO; GO:0030553; F:cGMP binding; ISS:UniProtKB.
DR   GO; GO:0004118; F:cGMP-stimulated cyclic-nucleotide phosphodiesterase activity; IDA:UniProtKB.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0042803; F:protein homodimerization activity; IBA:GO_Central.
DR   GO; GO:0019933; P:cAMP-mediated signaling; ISS:UniProtKB.
DR   GO; GO:0071321; P:cellular response to cGMP; ISS:UniProtKB.
DR   GO; GO:0097011; P:cellular response to granulocyte macrophage colony-stimulating factor stimulus; ISS:UniProtKB.
DR   GO; GO:0036006; P:cellular response to macrophage colony-stimulating factor stimulus; ISS:UniProtKB.
DR   GO; GO:0071260; P:cellular response to mechanical stimulus; ISS:UniProtKB.
DR   GO; GO:0046069; P:cGMP catabolic process; ISS:UniProtKB.
DR   GO; GO:0019934; P:cGMP-mediated signaling; ISS:UniProtKB.
DR   GO; GO:0061028; P:establishment of endothelial barrier; ISS:UniProtKB.
DR   GO; GO:0046038; P:GMP catabolic process; TAS:AgBase.
DR   GO; GO:0043951; P:negative regulation of cAMP-mediated signaling; ISS:UniProtKB.
DR   GO; GO:0010754; P:negative regulation of cGMP-mediated signaling; IBA:GO_Central.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR   GO; GO:0043116; P:negative regulation of vascular permeability; ISS:UniProtKB.
DR   GO; GO:0010628; P:positive regulation of gene expression; IBA:GO_Central.
DR   GO; GO:0050729; P:positive regulation of inflammatory response; ISS:UniProtKB.
DR   GO; GO:0043117; P:positive regulation of vascular permeability; ISS:UniProtKB.
DR   GO; GO:0043949; P:regulation of cAMP-mediated signaling; ISS:UniProtKB.
DR   GO; GO:0010821; P:regulation of mitochondrion organization; IBA:GO_Central.
DR   GO; GO:0007165; P:signal transduction; NAS:AgBase.
DR   CDD; cd00077; HDc; 1.
DR   Gene3D; 3.30.450.40; -; 2.
DR   Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1.
DR   InterPro; IPR003018; GAF.
DR   InterPro; IPR029016; GAF-like_dom_sf.
DR   InterPro; IPR003607; HD/PDEase_dom.
DR   InterPro; IPR023088; PDEase.
DR   InterPro; IPR002073; PDEase_catalytic_dom.
DR   InterPro; IPR036971; PDEase_catalytic_dom_sf.
DR   InterPro; IPR023174; PDEase_CS.
DR   PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1.
DR   PANTHER; PTHR11347:SF102; PHOSPHODIESTERASE; 1.
DR   Pfam; PF01590; GAF; 2.
DR   Pfam; PF00233; PDEase_I; 1.
DR   PRINTS; PR00387; PDIESTERASE1.
DR   SMART; SM00065; GAF; 2.
DR   SMART; SM00471; HDc; 1.
DR   SUPFAM; SSF55781; GAF domain-like; 3.
DR   SUPFAM; SSF109604; HD-domain/PDEase-like; 1.
DR   PROSITE; PS00126; PDEASE_I_1; 1.
DR   PROSITE; PS51845; PDEASE_I_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Alternative splicing; cAMP; Cell membrane; cGMP;
KW   cGMP-binding; Cytoplasm; Direct protein sequencing; Hydrolase; Magnesium;
KW   Membrane; Metal-binding; Mitochondrion; Mitochondrion inner membrane;
KW   Mitochondrion outer membrane; Nucleotide-binding; Reference proteome;
KW   Repeat; Zinc.
FT   CHAIN           1..921
FT                   /note="cGMP-dependent 3',5'-cyclic phosphodiesterase"
FT                   /id="PRO_0000198795"
FT   DOMAIN          220..357
FT                   /note="GAF 1"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          389..528
FT                   /note="GAF 2"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          558..882
FT                   /note="PDEase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT   REGION          1..21
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          177..198
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        636
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:O76083"
FT   BINDING         411
FT                   /ligand="3',5'-cyclic GMP"
FT                   /ligand_id="ChEBI:CHEBI:57746"
FT                   /ligand_note="allosteric activator"
FT                   /evidence="ECO:0000250|UniProtKB:Q922S4"
FT   BINDING         426
FT                   /ligand="3',5'-cyclic GMP"
FT                   /ligand_id="ChEBI:CHEBI:57746"
FT                   /ligand_note="allosteric activator"
FT                   /evidence="ECO:0000250|UniProtKB:Q922S4"
FT   BINDING         445
FT                   /ligand="3',5'-cyclic GMP"
FT                   /ligand_id="ChEBI:CHEBI:57746"
FT                   /ligand_note="allosteric activator"
FT                   /evidence="ECO:0000250|UniProtKB:Q922S4"
FT   BINDING         468
FT                   /ligand="3',5'-cyclic GMP"
FT                   /ligand_id="ChEBI:CHEBI:57746"
FT                   /ligand_note="allosteric activator"
FT                   /evidence="ECO:0000250|UniProtKB:Q922S4"
FT   BINDING         479
FT                   /ligand="3',5'-cyclic GMP"
FT                   /ligand_id="ChEBI:CHEBI:57746"
FT                   /ligand_note="allosteric activator"
FT                   /evidence="ECO:0000250|UniProtKB:Q922S4"
FT   BINDING         640
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:O00408"
FT   BINDING         676
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:O00408"
FT   BINDING         677
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:O00408"
FT   BINDING         677
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:O00408"
FT   BINDING         788
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /evidence="ECO:0000250|UniProtKB:O00408"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000269|PubMed:2176866"
FT   VAR_SEQ         1..25
FT                   /note="MRRQPAASRDLFAQEPVPPGSGDGA -> MGQACGHSILCRSQQYPAARPAE
FT                   PRGQQVFLKPDEPPPPPQPCADS (in isoform PDE2A3)"
FT                   /evidence="ECO:0000303|Ref.2"
FT                   /id="VSP_004555"
FT   CONFLICT        204
FT                   /note="N -> D (in Ref. 2; AAA87353)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        633
FT                   /note="P -> L (in Ref. 4; AA sequence)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   921 AA;  103228 MW;  E29F4C9875E83640 CRC64;
     MRRQPAASRD LFAQEPVPPG SGDGALQDAL LSLGSVIDVA GLQQAVKEAL SAVLPKVETV
     YTYLLDGESR LVCEEPPHEL PQEGKVREAV ISRKRLGCNG LGPSDLPGKP LARLVAPLAP
     DTQVLVIPLV DKEAGAVAAV ILVHCGQLSD NEEWSLQAVE KHTLVALKRV QALQQRESSV
     APEATQNPPE EAAGDQKGGV AYTNQDRKIL QLCGELYDLD ASSLQLKVLQ YLQQETQASR
     CCLLLVSEDN LQLSCKVIGD KVLEEEISFP LTTGRLGQVV EDKKSIQLKD LTSEDMQQLQ
     SMLGCEVQAM LCVPVISRAT DQVVALACAF NKLGGDLFTD QDEHVIQHCF HYTSTVLTST
     LAFQKEQKLK CECQALLQVA KNLFTHLDDV SVLLQEIITE ARNLSNAEIC SVFLLDQNEL
     VAKVFDGGVV EDESYEIRIP ADQGIAGHVA TTGQILNIPD AYAHPLFYRG VDDSTGFRTR
     NILCFPIKNE NQEVIGVAEL VNKINGPWFS KFDEDLATAF SIYCGISIAH SLLYKKVNEA
     QYRSHLANEM MMYHMKVSDD EYTKLLHDGI QPVAAIDSNF ASFTYTPRSL PEDDTSMAIL
     SMLQDMNFIN NYKIDCPTLA RFCLMVKKGY RDPPYHNWMH AFSVSHFCYL LYKNLELTNY
     LEDMEIFALF ISCMCHDLDH RGTNNSFQVA SKSVLAALYS SEGSVMERHH FAQAIAILNT
     HGCNIFDHFS RKDYQRMLDL MRDIILATDL AHHLRIFKDL QKMAEVGYDR TNKQHHSLLL
     CLLMTSCDLS DQTKGWKTTR KIAELIYKEF FSQGDLEKAM GNRPMEMMDR EKAYIPELQI
     SFMEHIAMPI YKLLQDLFPK AAELYERVAS NREHWTKVSH KFTIRGLPSN NSLDFLDEEY
     EVPDLDGARA PINGCCSLDA E
//