ID PDE2A_RAT Reviewed; 928 AA. AC Q01062; DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 2. DT 27-MAR-2024, entry version 167. DE RecName: Full=cGMP-dependent 3',5'-cyclic phosphodiesterase {ECO:0000250|UniProtKB:O00408}; DE EC=3.1.4.17 {ECO:0000250|UniProtKB:O00408}; DE AltName: Full=Cyclic GMP-stimulated phosphodiesterase {ECO:0000303|PubMed:7811274}; DE Short=CGS-PDE {ECO:0000303|PubMed:7811274}; DE Short=cGSPDE {ECO:0000303|PubMed:7811274}; GN Name=Pde2a {ECO:0000312|RGD:620965}; 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]. RC STRAIN=Sprague-Dawley; TISSUE=Brain; RX PubMed=7811274; DOI=10.1006/bbrc.1994.2886; RA Yang Q., Paskind M., Bolger G., Thompson W.J., Repaske D.R., Cutler L.S., RA Epstein P.M.; RT "A novel cyclic GMP stimulated phosphodiesterase from rat brain."; RL Biochem. Biophys. Res. Commun. 205:1850-1858(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] OF 643-759. RX PubMed=1326532; DOI=10.1016/s0021-9258(19)37015-2; RA Repaske D.R., Swinnen J.V., Jin S.-L.C., van Wyk J.J., Conti M.; RT "A polymerase chain reaction strategy to identify and clone cyclic RT nucleotide phosphodiesterase cDNAs. Molecular cloning of the cDNA encoding RT the 63-kDa calmodulin-dependent phosphodiesterase."; RL J. Biol. Chem. 267:18683-18688(1992). RN [3] RP SUBCELLULAR LOCATION (ISOFORM PDE2A2), AND TISSUE SPECIFICITY. RX PubMed=21724846; DOI=10.1074/jbc.m111.266379; RA Acin-Perez R., Russwurm M., Gunnewig K., Gertz M., Zoidl G., Ramos L., RA Buck J., Levin L.R., Rassow J., Manfredi G., Steegborn C.; RT "A phosphodiesterase 2A isoform localized to mitochondria regulates RT respiration."; RL J. Biol. Chem. 286:30423-30432(2011). RN [4] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-109, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22673903; DOI=10.1038/ncomms1871; RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., RA Olsen J.V.; RT "Quantitative maps of protein phosphorylation sites across 14 different rat RT organs and tissues."; RL Nat. Commun. 3:876-876(2012). RN [5] RP FUNCTION (ISOFORM PDE2A2), SUBCELLULAR LOCATION (ISOFORM PDE2A2), AND RP ACTIVITY REGULATION. RX PubMed=28463107; DOI=10.7554/elife.21374; RA Monterisi S., Lobo M.J., Livie C., Castle J.C., Weinberger M., Baillie G., RA Surdo N.C., Musheshe N., Stangherlin A., Gottlieb E., Maizels R., RA Bortolozzi M., Micaroni M., Zaccolo M.; RT "PDE2A2 regulates mitochondria morphology and apoptotic cell death via RT local modulation of cAMP/PKA signalling."; RL Elife 6:0-0(2017). 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. Has a higher CC efficiency with cGMP compared to cAMP (By similarity). Plays a role in CC cell growth and migration (By similarity). CC {ECO:0000250|UniProtKB:O00408}. CC -!- FUNCTION: [Isoform PDE2A2]: Regulates mitochondrial cAMP levels and CC respiration (By similarity). 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 (PubMed:28463107). CC {ECO:0000250|UniProtKB:Q922S4, ECO:0000269|PubMed:28463107}. 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:0000250|UniProtKB:O00408}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14654; CC Evidence={ECO:0000250|UniProtKB:O00408}; 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:0000250|UniProtKB:O00408}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958; CC Evidence={ECO:0000250|UniProtKB:O00408}; 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:0000250|UniProtKB:O00408}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25278; CC Evidence={ECO:0000250|UniProtKB:O00408}; CC -!- COFACTOR: CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000250|UniProtKB:O00408}; 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 (By similarity). Specifically inhibited CC by Bay 60-7550. When repressed, protected from ionomycin- but not CC staurosporin-induced cell death. {ECO:0000250|UniProtKB:O00408, CC ECO:0000269|PubMed:28463107}. CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:O00408}. CC -!- INTERACTION: CC Q01062; Q5FWY5: Aip; NbExp=2; IntAct=EBI-1786062, EBI-1786045; CC -!- SUBCELLULAR LOCATION: [Isoform PDE2A3]: Cell membrane CC {ECO:0000250|UniProtKB:O00408}; Peripheral membrane protein CC {ECO:0000305}. CC -!- SUBCELLULAR LOCATION: [Isoform PDE2A1]: Cytoplasm CC {ECO:0000250|UniProtKB:O00408}. CC -!- SUBCELLULAR LOCATION: [Isoform PDE2A2]: Mitochondrion matrix CC {ECO:0000269|PubMed:21724846}. Mitochondrion inner membrane CC {ECO:0000269|PubMed:28463107}. Mitochondrion outer membrane CC {ECO:0000269|PubMed:28463107}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Comment=Additional isoforms seem to exist. Experimental confirmation CC may be lacking for some isoforms.; CC Name=PDE2A3; CC IsoId=Q01062-1; Sequence=Displayed; CC Name=PDE2A1; CC IsoId=Q01062-2; Sequence=Not described; CC Name=PDE2A2; CC IsoId=Q01062-3; Sequence=Not described; CC -!- TISSUE SPECIFICITY: Expressed in brain and liver. CC {ECO:0000269|PubMed:21724846}. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U21101; AAA63683.1; -; mRNA. DR EMBL; M94540; AAA40922.1; -; mRNA. DR PIR; JC2486; JC2486. DR RefSeq; NP_001137319.1; NM_001143847.1. DR RefSeq; NP_112341.1; NM_031079.1. [Q01062-1] DR AlphaFoldDB; Q01062; -. DR SMR; Q01062; -. DR BioGRID; 249615; 4. DR IntAct; Q01062; 1. DR STRING; 10116.ENSRNOP00000026586; -. DR BindingDB; Q01062; -. DR ChEMBL; CHEMBL4650; -. DR DrugCentral; Q01062; -. DR iPTMnet; Q01062; -. DR PhosphoSitePlus; Q01062; -. DR SwissPalm; Q01062; -. DR PaxDb; 10116-ENSRNOP00000026586; -. DR GeneID; 81743; -. DR KEGG; rno:81743; -. DR UCSC; RGD:620965; rat. [Q01062-1] DR AGR; RGD:620965; -. DR CTD; 5138; -. DR RGD; 620965; Pde2a. DR eggNOG; KOG3689; Eukaryota. DR InParanoid; Q01062; -. DR OrthoDB; 5479253at2759; -. DR PhylomeDB; Q01062; -. DR BRENDA; 3.1.4.17; 5301. DR Reactome; R-RNO-418457; cGMP effects. DR Reactome; R-RNO-418555; G alpha (s) signalling events. DR SABIO-RK; Q01062; -. DR PRO; PR:Q01062; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0030424; C:axon; ISO:RGD. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:0030425; C:dendrite; ISO:RGD. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB. DR GO; GO:0097457; C:hippocampal mossy fiber; IDA:RGD. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB. DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. 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; IDA:UniProtKB. DR GO; GO:0042734; C:presynaptic membrane; ISS:UniProtKB. DR GO; GO:0097060; C:synaptic membrane; IDA:RGD. DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; ISS:UniProtKB. DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; ISO:RGD. DR GO; GO:0030552; F:cAMP binding; ISO:RGD. DR GO; GO:0030553; F:cGMP binding; ISO:RGD. DR GO; GO:0004118; F:cGMP-stimulated cyclic-nucleotide phosphodiesterase activity; ISO:RGD. DR GO; GO:0036004; F:GAF domain binding; ISO:RGD. DR GO; GO:0042802; F:identical protein binding; IPI:RGD. DR GO; GO:0000287; F:magnesium ion binding; ISO:RGD. DR GO; GO:0042301; F:phosphate ion binding; ISO:RGD. DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD. DR GO; GO:0030911; F:TPR domain binding; ISO:RGD. DR GO; GO:0008270; F:zinc ion binding; ISO:RGD. DR GO; GO:0007193; P:adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway; ISO:RGD. DR GO; GO:0035904; P:aorta development; ISO:RGD. DR GO; GO:0019933; P:cAMP-mediated signaling; ISO:RGD. DR GO; GO:0003279; P:cardiac septum development; ISO:RGD. DR GO; GO:1904613; P:cellular response to 2,3,7,8-tetrachlorodibenzodioxine; ISO:RGD. DR GO; GO:0071320; P:cellular response to cAMP; ISO:RGD. 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:0071222; P:cellular response to lipopolysaccharide; ISO:RGD. 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:0071560; P:cellular response to transforming growth factor beta stimulus; ISO:RGD. DR GO; GO:0046069; P:cGMP catabolic process; ISO:RGD. DR GO; GO:0019934; P:cGMP-mediated signaling; ISS:UniProtKB. DR GO; GO:0060976; P:coronary vasculature development; ISO:RGD. DR GO; GO:0061028; P:establishment of endothelial barrier; IDA:UniProtKB. DR GO; GO:0007507; P:heart development; ISO:RGD. DR GO; GO:0003170; P:heart valve development; ISO:RGD. DR GO; GO:0035556; P:intracellular signal transduction; IMP:UniProtKB. DR GO; GO:0043951; P:negative regulation of cAMP-mediated signaling; IDA:RGD. DR GO; GO:0010754; P:negative regulation of cGMP-mediated signaling; ISO:RGD. DR GO; GO:0090324; P:negative regulation of oxidative phosphorylation; ISO:RGD. 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; ISO:RGD. 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:0010752; P:regulation of cGMP-mediated signaling; ISO:RGD. DR GO; GO:0010821; P:regulation of mitochondrion organization; IMP:UniProtKB. DR GO; GO:0010749; P:regulation of nitric oxide mediated signal transduction; ISO:RGD. DR GO; GO:1904880; P:response to hydrogen sulfide; IEP:RGD. DR GO; GO:0003281; P:ventricular septum development; ISO:RGD. 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; 1. DR Pfam; PF13185; GAF_2; 1. DR Pfam; PF00233; PDEase_I; 1. DR PRINTS; PR00387; PDIESTERASE1. DR SMART; SM00065; GAF; 3. 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 Alternative splicing; cAMP; Cell membrane; cGMP; cGMP-binding; Cytoplasm; KW Hydrolase; Magnesium; Membrane; Metal-binding; Mitochondrion; KW Mitochondrion inner membrane; Mitochondrion outer membrane; KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat; Zinc. FT CHAIN 1..928 FT /note="cGMP-dependent 3',5'-cyclic phosphodiesterase" FT /id="PRO_0000198798" FT DOMAIN 228..365 FT /note="GAF 1" FT /evidence="ECO:0000255" FT DOMAIN 397..536 FT /note="GAF 2" FT /evidence="ECO:0000255" FT DOMAIN 566..890 FT /note="PDEase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192" FT REGION 188..210 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 644 FT /note="Proton donor" FT /evidence="ECO:0000250|UniProtKB:O76083" FT BINDING 419 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 434 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 453 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 476 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 487 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 648 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O00408" FT BINDING 684 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O00408" FT BINDING 685 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250|UniProtKB:O00408" FT BINDING 685 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O00408" FT BINDING 796 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250|UniProtKB:O00408" FT MOD_RES 109 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT CONFLICT 646 FT /note="W -> R (in Ref. 2; AAA40922)" FT /evidence="ECO:0000305" FT CONFLICT 758 FT /note="L -> M (in Ref. 2; AAA40922)" FT /evidence="ECO:0000305" SQ SEQUENCE 928 AA; 104664 MW; EF0B8C1E266EAB18 CRC64; MVLVLHHILI AVVQFLRRGQ QVFLKPDEPP PQPCADSLQD ALLSLGAVID IAGLRQAAKD ALSAVLPKVE TVYTYLVDGE SRLVCEDPPH ELPQEGKIRE AVISRKRLSC DGLGPSDLLG KPLARLVAPL APDTQVLVIP LLDKETGTVA AVILVHCGQL SDSEEQSLQV VEKHALVALQ RVQALQQRRP EAVQNTSADP SEDQKDEKGY TAHDRKILQL CGELYDLDAT SLQLKVLRYL QQETQATHCC LLLVSEDNLQ LSCKVIGEKV LGEEVSFPLT MGRLGQVVED KQCIQLKDLT SDDVQQLQNM LGCELRAMLC VPVISRATDQ VVALACAFNK LGGDFFTDED ERAIQHCFHY TGTVLTSTLA FQKEQKLKCE CQALLQVAKN LFTHLDDVSV LLQEIITEAR NLSNAEICSV FLLDQNELVA KVFDGGVVDD ESYEIRIPAD QGIAGHVATT GQILNIPDAY AHPLFYRGVD DSTGFRTRNI LCFPIKNENQ EVIGVAELVN KINGPWFSKF DEDLATAFSI YCGISIAHSL LYKKVNEAQY RSHLANEMMM YHMKVSDDEY TKLLHDGIQP VAAIDSNFAN FTYTPRSLPE DDTSMAILSM LQDMNFINNY KIDCPTLARF CLMVKKGYRD PPYHNWMHAF SVSHFCYLLY KNLELSNYLE DIEIFALFIS CMCHDLDHRG TNNSFQVASK SVLAALYSSE GSVMERHHFA QAIAILNTHG CNIFDHFSRK DYQRMLDLMR DIILATDLAH HLRIFKDLQK MAEVGYDRNN KQHHRLLLCL LMTSCDLSDQ TKGWKTTRKI AELIYKEFFS QGDLEKAMGN RPMEMMDREK AYIPELQISF MEHIAMPIYK LLQDLFPKAA ELYERVASNR EHWTKVSHKF TIRGLPSNNS LDFLDEEYEV PDLDVTRAPV NGCCSLEG //