PDE2A_RAT
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 03-AUG-2022, entry version 160.
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}.
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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; Q01062; -.
DR PRIDE; Q01062; -.
DR GeneID; 81743; -.
DR KEGG; rno:81743; -.
DR UCSC; RGD:620965; rat. [Q01062-1]
DR CTD; 5138; -.
DR RGD; 620965; Pde2a.
DR eggNOG; KOG3689; Eukaryota.
DR InParanoid; Q01062; -.
DR OrthoDB; 904682at2759; -.
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:0045121; C:membrane raft; 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; IDA:RGD.
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:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
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:0043951; P:negative regulation of cAMP-mediated signaling; IDA:RGD.
DR GO; GO:0060548; P:negative regulation of cell death; IMP:UniProtKB.
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:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0003281; P:ventricular septum development; ISO:RGD.
DR CDD; cd00077; HDc; 1.
DR Gene3D; 1.10.1300.10; -; 1.
DR Gene3D; 3.30.450.40; -; 2.
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 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 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
