PDE3A_HUMAN
ID PDE3A_HUMAN Reviewed; 1141 AA.
AC Q14432; O60865; Q13348; Q17RD1;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2004, sequence version 3.
DT 03-AUG-2022, entry version 191.
DE RecName: Full=cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A {ECO:0000305|PubMed:8155697};
DE EC=3.1.4.17 {ECO:0000269|PubMed:1315035, ECO:0000269|PubMed:25961942, ECO:0000269|PubMed:8155697, ECO:0000269|PubMed:8695850};
DE AltName: Full=Cyclic GMP-inhibited phosphodiesterase A;
DE Short=CGI-PDE A;
DE AltName: Full=cGMP-inhibited cAMP phosphodiesterase {ECO:0000303|PubMed:8155697};
DE Short=cGI-PDE {ECO:0000303|PubMed:8155697};
GN Name=PDE3A {ECO:0000312|HGNC:HGNC:8778};
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], FUNCTION, AND CATALYTIC ACTIVITY.
RC TISSUE=Myocardium;
RX PubMed=1315035; DOI=10.1073/pnas.89.9.3721;
RA Meacci E., Taira M., Moos M. Jr., Smith C.J., Movsesian M.A., Degerman E.,
RA Belfrage P., Manganiello V.;
RT "Molecular cloning and expression of human myocardial cGMP-inhibited cAMP
RT phosphodiesterase.";
RL Proc. Natl. Acad. Sci. U.S.A. 89:3721-3725(1992).
RN [2]
RP SEQUENCE REVISION TO 12; 63-64 AND 354-371.
RA Liu H., Manganiello V.;
RL Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT ASN-12, FUNCTION, CATALYTIC ACTIVITY,
RP AND ACTIVITY REGULATION.
RC TISSUE=Blood;
RX PubMed=8695850;
RA Cheung P.P., Xu H., McLaughlin M.M., Ghazaleh F.A., Livi G.P., Colman R.W.;
RT "Human platelet cGI-PDE: expression in yeast and localization of the
RT catalytic domain by deletion mutagenesis.";
RL Blood 88:1321-1329(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Penis;
RX PubMed=10421499; DOI=10.1016/s0009-2797(99)00074-5;
RA Kuthe A., Eckel H., Stief C.G., Uckert S., Forssmann W.-G., Jonas U.,
RA Maegert H.-J.;
RT "Molecular biological characterization of phosphodiesterase 3A from human
RT corpus cavernosum.";
RL Chem. Biol. Interact. 119:593-598(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, ACTIVITY REGULATION, AND SUBUNIT.
RX PubMed=8155697; DOI=10.1016/0167-4838(94)90233-x;
RA Degerman E., Moos M. Jr., Rascon A., Vasta V., Meacci E., Smith C.J.,
RA Lindgren S., Andersson K.-E., Belfrage P., Manganiello V.;
RT "Single-step affinity purification, partial structure and properties of
RT human platelet cGMP inhibited cAMP phosphodiesterase.";
RL Biochim. Biophys. Acta 1205:189-198(1994).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-520, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-312, AND IDENTIFICATION BY
RP 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 [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-312; SER-492 AND SER-520, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [12]
RP INVOLVEMENT IN HTNB, VARIANTS HTNB ALA-445; ASN-445; SER-445; THR-447;
RP VAL-447 AND VAL-449, CHARACTERIZATION OF VARIANTS HTNB ALA-445; ASN-445;
RP SER-445; THR-447; VAL-447 AND VAL-449, FUNCTION, CATALYTIC ACTIVITY, AND
RP PHOSPHORYLATION AT SER-428 AND SER-438.
RX PubMed=25961942; DOI=10.1038/ng.3302;
RA Maass P.G., Aydin A., Luft F.C., Schaechterle C., Weise A., Stricker S.,
RA Lindschau C., Vaegler M., Qadri F., Toka H.R., Schulz H., Krawitz P.M.,
RA Parkhomchuk D., Hecht J., Hollfinger I., Wefeld-Neuenfeld Y.,
RA Bartels-Klein E., Muehl A., Kann M., Schuster H., Chitayat D., Bialer M.G.,
RA Wienker T.F., Ott J., Rittscher K., Liehr T., Jordan J., Plessis G.,
RA Tank J., Mai K., Naraghi R., Hodge R., Hopp M., Hattenbach L.O.,
RA Busjahn A., Rauch A., Vandeput F., Gong M., Rueschendorf F., Huebner N.,
RA Haller H., Mundlos S., Bilginturan N., Movsesian M.A., Klussmann E.,
RA Toka O., Baehring S.;
RT "PDE3A mutations cause autosomal dominant hypertension with
RT brachydactyly.";
RL Nat. Genet. 47:647-653(2015).
RN [13]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-1120, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RX PubMed=27975297; DOI=10.1007/s00210-016-1328-1;
RA Berrisch S., Ostermeyer J., Kaever V., Kaelble S., Hilfiker-Kleiner D.,
RA Seifert R., Schneider E.H.;
RT "cUMP hydrolysis by PDE3A.";
RL Naunyn Schmiedebergs Arch. Pharmacol. 390:269-280(2017).
RN [15]
RP FUNCTION, AND INTERACTION WITH SLFN12.
RX PubMed=31420216; DOI=10.1016/j.molcel.2019.06.040;
RA Li D., Chen J., Ai Y., Gu X., Li L., Che D., Jiang Z., Li L., Chen S.,
RA Huang H., Wang J., Cai T., Cao Y., Qi X., Wang X.;
RT "Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12
RT Protein Turnover.";
RL Mol. Cell 75:1103-1116(2019).
RN [16]
RP ACTIVITY REGULATION, INTERACTION WITH SLFN12, SUBCELLULAR LOCATION, AND
RP REGION.
RX PubMed=35104454; DOI=10.1016/j.chembiol.2022.01.006;
RA Yan B., Ding Z., Zhang W., Cai G., Han H., Ma Y., Cao Y., Wang J., Chen S.,
RA Ai Y.;
RT "Multiple PDE3A modulators act as molecular glues promoting PDE3A-SLFN12
RT interaction and induce SLFN12 dephosphorylation and cell death.";
RL Cell Chem. Biol. 0:0-0(2022).
RN [17] {ECO:0007744|PDB:7KWE, ECO:0007744|PDB:7L27, ECO:0007744|PDB:7L28, ECO:0007744|PDB:7L29, ECO:0007744|PDB:7LRC, ECO:0007744|PDB:7LRD}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 669-1095 IN COMPLEX WITH SLFN12
RP AND AMP; MAGNESIUM AND MANGANESE, COFACTOR, SUBUNIT, AND MUTAGENESIS OF
RP ASN-867 AND PHE-914.
RX PubMed=34272366; DOI=10.1038/s41467-021-24495-w;
RA Garvie C.W., Wu X., Papanastasiou M., Lee S., Fuller J., Schnitzler G.R.,
RA Horner S.W., Baker A., Zhang T., Mullahoo J.P., Westlake L., Hoyt S.H.,
RA Toetzl M., Ranaghan M.J., de Waal L., McGaunn J., Kaplan B., Piccioni F.,
RA Yang X., Lange M., Tersteegen A., Raymond D., Lewis T.A., Carr S.A.,
RA Cherniack A.D., Lemke C.T., Meyerson M., Greulich H.;
RT "Structure of PDE3A-SLFN12 complex reveals requirements for activation of
RT SLFN12 RNase.";
RL Nat. Commun. 12:4375-4375(2021).
RN [18] {ECO:0007744|PDB:7EG0, ECO:0007744|PDB:7EG4}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) OF 669-1102 IN COMPLEX
RP WITH SLFN12, AND FUNCTION.
RX PubMed=34707099; DOI=10.1038/s41467-021-26546-8;
RA Chen J., Liu N., Huang Y., Wang Y., Sun Y., Wu Q., Li D., Gao S.,
RA Wang H.W., Huang N., Qi X., Wang X.;
RT "Structure of PDE3A-SLFN12 complex and structure-based design for a potent
RT apoptosis inducer of tumor cells.";
RL Nat. Commun. 12:6204-6204(2021).
CC -!- FUNCTION: Cyclic nucleotide phosphodiesterase with specificity for the
CC second messengers cAMP and cGMP, which are key regulators of many
CC important physiological processes (PubMed:1315035, PubMed:8695850,
CC PubMed:8155697, PubMed:25961942). Has also activity toward cUMP
CC (PubMed:27975297). Independently of its catalytic activity it is part
CC of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2
CC stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the
CC dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal
CC RNA/rRNA ribonuclease activity. This apoptotic pathway might be
CC relevant in tissues with high concentration of E2 and be for instance
CC involved in placenta remodeling (PubMed:31420216, PubMed:34707099).
CC {ECO:0000269|PubMed:1315035, ECO:0000269|PubMed:25961942,
CC ECO:0000269|PubMed:27975297, ECO:0000269|PubMed:31420216,
CC ECO:0000269|PubMed:34707099, ECO:0000269|PubMed:8155697,
CC ECO:0000269|PubMed:8695850}.
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:1315035, ECO:0000269|PubMed:25961942,
CC ECO:0000269|PubMed:8155697, ECO:0000269|PubMed:8695850};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14654;
CC Evidence={ECO:0000305|PubMed:25961942};
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:1315035,
CC ECO:0000269|PubMed:25961942, ECO:0000269|PubMed:8155697,
CC ECO:0000269|PubMed:8695850};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25278;
CC Evidence={ECO:0000305|PubMed:25961942};
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:8155697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958;
CC Evidence={ECO:0000305|PubMed:8155697};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3',5'-cyclic UMP + H2O = H(+) + UMP; Xref=Rhea:RHEA:70575,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57865,
CC ChEBI:CHEBI:184387; Evidence={ECO:0000269|PubMed:27975297};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70576;
CC Evidence={ECO:0000305|PubMed:27975297};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:34272366};
CC Note=Binds 2 divalent metal cations per subunit.
CC {ECO:0000269|PubMed:34272366};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:34272366};
CC Note=Binds 2 divalent metal cations per subunit.
CC {ECO:0000269|PubMed:34272366};
CC -!- ACTIVITY REGULATION: Inhibited by cGMP (PubMed:8695850,
CC PubMed:8155697). Inhibited by 17beta-estradiol (PubMed:35104454).
CC Inhibited by milrinone (PubMed:27975297). {ECO:0000269|PubMed:27975297,
CC ECO:0000269|PubMed:35104454, ECO:0000269|PubMed:8155697,
CC ECO:0000269|PubMed:8695850}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.20 uM for 3',5'-cyclic AMP {ECO:0000269|PubMed:8155697};
CC KM=0.30 uM for 3',5'-cyclic GMP {ECO:0000269|PubMed:8155697};
CC KM=98.8 uM for 3',5'-cyclic UMP {ECO:0000269|PubMed:27975297};
CC Vmax=6.1 umol/min/mg enzyme with 3',5'-cyclic AMP as substrate
CC {ECO:0000269|PubMed:8155697};
CC Vmax=0.9 umol/min/mg enzyme with 3',5'-cyclic GMP as substrate
CC {ECO:0000269|PubMed:8155697};
CC Vmax=38.6 umol/min/mg enzyme with 3',5'-cyclic UMP as substrate
CC {ECO:0000269|PubMed:8155697};
CC -!- SUBUNIT: Homodimer (PubMed:8155697, PubMed:34272366). Interacts with
CC SLFN12; direct low affinity interaction which is stimulated by binding
CC of 17beta-estradiol/E2 to PDE3A and that positively regulates the
CC ribonuclease activity of SLFN12 (PubMed:31420216, PubMed:35104454,
CC PubMed:34272366, PubMed:34707099). {ECO:0000269|PubMed:31420216,
CC ECO:0000269|PubMed:34272366, ECO:0000269|PubMed:34707099,
CC ECO:0000269|PubMed:35104454, ECO:0000269|PubMed:8155697}.
CC -!- INTERACTION:
CC Q14432; Q9Y6D6: ARFGEF1; NbExp=6; IntAct=EBI-7192066, EBI-1044254;
CC Q14432; Q9Y6D5: ARFGEF2; NbExp=5; IntAct=EBI-7192066, EBI-2837511;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:Q9Z0X4}; Multi-
CC pass membrane protein {ECO:0000255}. Cytoplasm, cytosol
CC {ECO:0000269|PubMed:35104454}.
CC -!- DISEASE: Hypertension and brachydactyly syndrome (HTNB) [MIM:112410]: A
CC syndrome characterized by brachydactyly type E, severe salt-independent
CC but age-dependent hypertension, an increased fibroblast growth rate,
CC neurovascular contact at the rostral-ventrolateral medulla, and altered
CC baroreflex blood pressure regulation. It results in death from stroke
CC before age 50 years when untreated. Brachydactyly type E is
CC characterized by shortening of the fingers mainly in the metacarpals
CC and metatarsals. {ECO:0000269|PubMed:25961942}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE3 subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=PDE3 entry;
CC URL="https://en.wikipedia.org/wiki/PDE3";
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DR EMBL; M91667; AAA35912.2; -; mRNA.
DR EMBL; U36798; AAB18673.1; -; mRNA.
DR EMBL; AJ005036; CAA06304.1; -; mRNA.
DR EMBL; BC117369; AAI17370.1; -; mRNA.
DR EMBL; BC117371; AAI17372.1; -; mRNA.
DR CCDS; CCDS31754.1; -.
DR PIR; A44093; A44093.
DR RefSeq; NP_000912.3; NM_000921.4.
DR PDB; 7EG0; EM; 3.40 A; A/C=669-1102.
DR PDB; 7EG1; EM; 3.20 A; A/C=669-1102.
DR PDB; 7EG4; EM; 3.20 A; A/C=669-1102.
DR PDB; 7KWE; X-ray; 2.00 A; A/B/C/D=669-779, A/B/C/D=801-1028, A/B/C/D=1068-1095.
DR PDB; 7L27; X-ray; 1.70 A; A/B/C/D=669-779, A/B/C/D=801-1028, A/B/C/D=1068-1095.
DR PDB; 7L28; X-ray; 2.20 A; A/B/C/D=669-779, A/B/C/D=801-1028, A/B/C/D=1068-1095.
DR PDB; 7L29; X-ray; 2.08 A; A/B/C/D=669-779, A/B/C/D=801-1028, A/B/C/D=1068-1095.
DR PDB; 7LRC; EM; 2.97 A; B/C=640-1141.
DR PDB; 7LRD; EM; 3.22 A; B/D=640-1141.
DR PDBsum; 7EG0; -.
DR PDBsum; 7EG1; -.
DR PDBsum; 7EG4; -.
DR PDBsum; 7KWE; -.
DR PDBsum; 7L27; -.
DR PDBsum; 7L28; -.
DR PDBsum; 7L29; -.
DR PDBsum; 7LRC; -.
DR PDBsum; 7LRD; -.
DR AlphaFoldDB; Q14432; -.
DR SMR; Q14432; -.
DR BioGRID; 111165; 77.
DR DIP; DIP-42197N; -.
DR IntAct; Q14432; 19.
DR MINT; Q14432; -.
DR STRING; 9606.ENSP00000351957; -.
DR BindingDB; Q14432; -.
DR ChEMBL; CHEMBL241; -.
DR DrugBank; DB01223; Aminophylline.
DR DrugBank; DB01427; Amrinone.
DR DrugBank; DB00261; Anagrelide.
DR DrugBank; DB00201; Caffeine.
DR DrugBank; DB01166; Cilostazol.
DR DrugBank; DB04880; Enoximone.
DR DrugBank; DB05266; Ibudilast.
DR DrugBank; DB00922; Levosimendan.
DR DrugBank; DB00235; Milrinone.
DR DrugBank; DB01303; Oxtriphylline.
DR DrugBank; DB00277; Theophylline.
DR DrugBank; DB08811; Tofisopam.
DR DrugBank; DB09283; Trapidil.
DR DrugCentral; Q14432; -.
DR GuidetoPHARMACOLOGY; 1298; -.
DR GlyGen; Q14432; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q14432; -.
DR PhosphoSitePlus; Q14432; -.
DR BioMuta; PDE3A; -.
DR DMDM; 47117888; -.
DR EPD; Q14432; -.
DR jPOST; Q14432; -.
DR MassIVE; Q14432; -.
DR MaxQB; Q14432; -.
DR PaxDb; Q14432; -.
DR PeptideAtlas; Q14432; -.
DR PRIDE; Q14432; -.
DR ProteomicsDB; 59987; -.
DR Antibodypedia; 2869; 232 antibodies from 32 providers.
DR DNASU; 5139; -.
DR Ensembl; ENST00000359062.4; ENSP00000351957.3; ENSG00000172572.7.
DR GeneID; 5139; -.
DR KEGG; hsa:5139; -.
DR MANE-Select; ENST00000359062.4; ENSP00000351957.3; NM_000921.5; NP_000912.3.
DR UCSC; uc001reh.3; human.
DR CTD; 5139; -.
DR DisGeNET; 5139; -.
DR GeneCards; PDE3A; -.
DR HGNC; HGNC:8778; PDE3A.
DR HPA; ENSG00000172572; Tissue enhanced (heart).
DR MalaCards; PDE3A; -.
DR MIM; 112410; phenotype.
DR MIM; 123805; gene.
DR neXtProt; NX_Q14432; -.
DR OpenTargets; ENSG00000172572; -.
DR Orphanet; 1276; Brachydactyly-arterial hypertension syndrome.
DR PharmGKB; PA33126; -.
DR VEuPathDB; HostDB:ENSG00000172572; -.
DR eggNOG; ENOG502QSV8; Eukaryota.
DR GeneTree; ENSGT00940000156628; -.
DR HOGENOM; CLU_008844_0_0_1; -.
DR OMA; CRGCWGD; -.
DR OrthoDB; 1051097at2759; -.
DR PhylomeDB; Q14432; -.
DR TreeFam; TF329631; -.
DR BRENDA; 3.1.4.17; 2681.
DR PathwayCommons; Q14432; -.
DR Reactome; R-HSA-418555; G alpha (s) signalling events.
DR SABIO-RK; Q14432; -.
DR SignaLink; Q14432; -.
DR SIGNOR; Q14432; -.
DR BioGRID-ORCS; 5139; 15 hits in 1072 CRISPR screens.
DR ChiTaRS; PDE3A; human.
DR GenomeRNAi; 5139; -.
DR Pharos; Q14432; Tclin.
DR PRO; PR:Q14432; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q14432; protein.
DR Bgee; ENSG00000172572; Expressed in heart right ventricle and 144 other tissues.
DR Genevisible; Q14432; HS.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0004119; F:cGMP-inhibited cyclic-nucleotide phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0099130; F:estrogen binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0097190; P:apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0019933; P:cAMP-mediated signaling; IMP:UniProtKB.
DR GO; GO:0071321; P:cellular response to cGMP; IDA:UniProtKB.
DR GO; GO:0071560; P:cellular response to transforming growth factor beta stimulus; IEP:UniProtKB.
DR GO; GO:0019934; P:cGMP-mediated signaling; IMP:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:Reactome.
DR GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0043951; P:negative regulation of cAMP-mediated signaling; IMP:UniProtKB.
DR GO; GO:0043116; P:negative regulation of vascular permeability; IMP:UniProtKB.
DR GO; GO:0001556; P:oocyte maturation; IBA:GO_Central.
DR GO; GO:0060282; P:positive regulation of oocyte development; IBA:GO_Central.
DR GO; GO:0043117; P:positive regulation of vascular permeability; IMP:UniProtKB.
DR GO; GO:0040020; P:regulation of meiotic nuclear division; IEA:Ensembl.
DR GO; GO:0060700; P:regulation of ribonuclease activity; IDA:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00077; HDc; 1.
DR Gene3D; 1.10.1300.10; -; 1.
DR InterPro; IPR003607; HD/PDEase_dom.
DR InterPro; IPR002073; PDEase_catalytic_dom.
DR InterPro; IPR036971; PDEase_catalytic_dom_sf.
DR InterPro; IPR023174; PDEase_CS.
DR Pfam; PF00233; PDEase_I; 1.
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 3D-structure; cAMP; cGMP; Cytoplasm; Direct protein sequencing;
KW Disease variant; Hydrolase; Isopeptide bond; Manganese; Membrane;
KW Metal-binding; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..1141
FT /note="cGMP-inhibited 3',5'-cyclic phosphodiesterase 3A"
FT /id="PRO_0000198799"
FT TRANSMEM 61..81
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 130..150
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 160..180
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 185..205
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 210..230
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 232..252
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 674..1093
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 1..42
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 436..482
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 590..640
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 669..1141
FT /note="Interaction with SLFN12"
FT /evidence="ECO:0000269|PubMed:35104454"
FT REGION 1023..1062
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1100..1141
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 436..451
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 467..482
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 608..636
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1031..1052
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1100..1115
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1116..1141
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 752
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 752
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7L29"
FT BINDING 756
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7KWE, ECO:0007744|PDB:7L27,
FT ECO:0007744|PDB:7L28, ECO:0007744|PDB:7L29"
FT BINDING 836
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7KWE, ECO:0007744|PDB:7L27,
FT ECO:0007744|PDB:7L28, ECO:0007744|PDB:7L29"
FT BINDING 837
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7L29"
FT BINDING 837
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7KWE, ECO:0007744|PDB:7L27,
FT ECO:0007744|PDB:7L28, ECO:0007744|PDB:7L29"
FT BINDING 837
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7KWE, ECO:0007744|PDB:7L27,
FT ECO:0007744|PDB:7L28, ECO:0007744|PDB:7L29"
FT BINDING 950
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7L29"
FT BINDING 950
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7KWE, ECO:0007744|PDB:7L27,
FT ECO:0007744|PDB:7L28, ECO:0007744|PDB:7L29"
FT BINDING 1001
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:34272366,
FT ECO:0007744|PDB:7L29"
FT MOD_RES 312
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 428
FT /note="Phosphoserine; by PKA and PKC"
FT /evidence="ECO:0000269|PubMed:25961942"
FT MOD_RES 438
FT /note="Phosphoserine; by PKA and PKC"
FT /evidence="ECO:0000269|PubMed:25961942"
FT MOD_RES 492
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 520
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 524
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X4"
FT MOD_RES 1033
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X4"
FT MOD_RES 1036
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0X4"
FT CROSSLNK 1120
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VARIANT 12
FT /note="D -> N (in dbSNP:rs12305038)"
FT /evidence="ECO:0000269|PubMed:8695850"
FT /id="VAR_059543"
FT VARIANT 445
FT /note="T -> A (in HTNB; increased 3',5'-cyclic-AMP
FT phosphodiesterase activity; increased function in cAMP-
FT mediated signaling; dbSNP:rs794726865)"
FT /evidence="ECO:0000269|PubMed:25961942"
FT /id="VAR_073869"
FT VARIANT 445
FT /note="T -> N (in HTNB; increased phosphorylation at S-428
FT and S-438; increased affinity for 3',5'-cyclic-AMP; no
FT effect on protein reaction kinetics for 3',5'-cyclic-AMP
FT phosphodiesterase activity; increased 3',5'-cyclic-AMP
FT phosphodiesterase activity; no effect on inhibition by
FT 3',5'-cyclic-GMP; changed function in cAMP-mediated
FT signaling; dbSNP:rs794726864)"
FT /evidence="ECO:0000269|PubMed:25961942"
FT /id="VAR_073870"
FT VARIANT 445
FT /note="T -> S (in HTNB; increased 3',5'-cyclic-AMP
FT phosphodiesterase activity; changed function in cAMP-
FT mediated signaling; dbSNP:rs794726864)"
FT /evidence="ECO:0000269|PubMed:25961942"
FT /id="VAR_073871"
FT VARIANT 447
FT /note="A -> T (in HTNB; increased 3',5'-cyclic-AMP
FT phosphodiesterase activity; changed function in cAMP-
FT mediated signaling; dbSNP:rs794726866)"
FT /evidence="ECO:0000269|PubMed:25961942"
FT /id="VAR_073872"
FT VARIANT 447
FT /note="A -> V (in HTNB; increased 3',5'-cyclic-AMP
FT phosphodiesterase activity; changed function in cAMP-
FT mediated signaling; dbSNP:rs794726867)"
FT /evidence="ECO:0000269|PubMed:25961942"
FT /id="VAR_073873"
FT VARIANT 449
FT /note="G -> V (in HTNB; increased 3',5'-cyclic-AMP
FT phosphodiesterase activity; changed function in cAMP-
FT mediated signaling; dbSNP:rs794726868)"
FT /evidence="ECO:0000269|PubMed:25961942"
FT /id="VAR_073874"
FT MUTAGEN 867
FT /note="N->R: Loss of interaction with SLFN12."
FT /evidence="ECO:0000269|PubMed:34272366"
FT MUTAGEN 914
FT /note="F->D,A: Loss of interaction with SLFN12."
FT /evidence="ECO:0000269|PubMed:34272366"
FT CONFLICT 69
FT /note="S -> C (in Ref. 3; AAB18673)"
FT /evidence="ECO:0000305"
FT CONFLICT 110
FT /note="G -> A (in Ref. 3; AAB18673)"
FT /evidence="ECO:0000305"
FT CONFLICT 354..371
FT /note="HGLITDLLADPSLPPNVC -> TASLPTSWQTLLFHQTCA (in Ref. 3
FT and 4; CAA06304)"
FT /evidence="ECO:0000305"
FT STRAND 675..678
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 680..682
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 683..686
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 687..690
FT /evidence="ECO:0007829|PDB:7L27"
FT STRAND 691..693
FT /evidence="ECO:0007829|PDB:7LRC"
FT HELIX 696..703
FT /evidence="ECO:0007829|PDB:7L27"
FT TURN 705..707
FT /evidence="ECO:0007829|PDB:7LRC"
FT HELIX 710..721
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 724..727
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 732..744
FT /evidence="ECO:0007829|PDB:7L27"
FT STRAND 750..753
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 754..769
FT /evidence="ECO:0007829|PDB:7L27"
FT STRAND 812..815
FT /evidence="ECO:0007829|PDB:7LRC"
FT HELIX 817..819
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 823..835
FT /evidence="ECO:0007829|PDB:7L27"
FT TURN 836..839
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 845..850
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 854..858
FT /evidence="ECO:0007829|PDB:7L27"
FT TURN 859..861
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 864..879
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 881..883
FT /evidence="ECO:0007829|PDB:7L27"
FT TURN 885..888
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 891..906
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 910..912
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 913..925
FT /evidence="ECO:0007829|PDB:7L27"
FT STRAND 926..928
FT /evidence="ECO:0007829|PDB:7L27"
FT STRAND 932..934
FT /evidence="ECO:0007829|PDB:7EG4"
FT HELIX 935..950
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 953..955
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 958..981
FT /evidence="ECO:0007829|PDB:7L27"
FT STRAND 992..994
FT /evidence="ECO:0007829|PDB:7LRC"
FT HELIX 997..1007
FT /evidence="ECO:0007829|PDB:7L27"
FT HELIX 1009..1018
FT /evidence="ECO:0007829|PDB:7L27"
FT STRAND 1025..1027
FT /evidence="ECO:0007829|PDB:7LRC"
FT STRAND 1070..1072
FT /evidence="ECO:0007829|PDB:7LRC"
FT HELIX 1074..1091
FT /evidence="ECO:0007829|PDB:7L27"
SQ SEQUENCE 1141 AA; 124979 MW; E69504130F39EFEA CRC64;
MAVPGDAARV RDKPVHSGVS QAPTAGRDCH HRADPASPRD SGCRGCWGDL VLQPLRSSRK
LSSALCAGSL SFLLALLVRL VRGEVGCDLE QCKEAAAAEE EEAAPGAEGG VFPGPRGGAP
GGGARLSPWL QPSALLFSLL CAFFWMGLYL LRAGVRLPLA VALLAACCGG EALVQIGLGV
GEDHLLSLPA AGVVLSCLAA ATWLVLRLRL GVLMIALTSA VRTVSLISLE RFKVAWRPYL
AYLAGVLGIL LARYVEQILP QSAEAAPREH LGSQLIAGTK EDIPVFKRRR RSSSVVSAEM
SGCSSKSHRR TSLPCIPREQ LMGHSEWDHK RGPRGSQSSG TSITVDIAVM GEAHGLITDL
LADPSLPPNV CTSLRAVSNL LSTQLTFQAI HKPRVNPVTS LSENYTCSDS EESSEKDKLA
IPKRLRRSLP PGLLRRVSST WTTTTSATGL PTLEPAPVRR DRSTSIKLQE APSSSPDSWN
NPVMMTLTKS RSFTSSYAIS AANHVKAKKQ SRPGALAKIS PLSSPCSSPL QGTPASSLVS
KISAVQFPES ADTTAKQSLG SHRALTYTQS APDLSPQILT PPVICSSCGR PYSQGNPADE
PLERSGVATR TPSRTDDTAQ VTSDYETNNN SDSSDIVQNE DETECLREPL RKASACSTYA
PETMMFLDKP ILAPEPLVMD NLDSIMEQLN TWNFPIFDLV ENIGRKCGRI LSQVSYRLFE
DMGLFEAFKI PIREFMNYFH ALEIGYRDIP YHNRIHATDV LHAVWYLTTQ PIPGLSTVIN
DHGSTSDSDS DSGFTHGHMG YVFSKTYNVT DDKYGCLSGN IPALELMALY VAAAMHDYDH
PGRTNAFLVA TSAPQAVLYN DRSVLENHHA AAAWNLFMSR PEYNFLINLD HVEFKHFRFL
VIEAILATDL KKHFDFVAKF NGKVNDDVGI DWTNENDRLL VCQMCIKLAD INGPAKCKEL
HLQWTDGIVN EFYEQGDEEA SLGLPISPFM DRSAPQLANL QESFISHIVG PLCNSYDSAG
LMPGKWVEDS DESGDTDDPE EEEEEAPAPN EEETCENNES PKKKTFKRRK IYCQITQHLL
QNHKMWKKVI EEEQRLAGIE NQSLDQTPQS HSSEQIQAIK EEEEEKGKPR GEEIPTQKPD
Q
