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 02-SEP-2026, entry version 209. 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; DOI=10.1182/blood.v88.4.1321.bloodjournal8841321; 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:25961942, CC PubMed:8155697, PubMed:8695850). Also has 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 = UMP + H(+); 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:8155697, CC PubMed:8695850). 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=0.2 uM for 3',5'-cyclic AMP {ECO:0000269|PubMed:8155697}; CC KM=0.3 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:34272366, PubMed:8155697). 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:34272366, CC PubMed:34707099, PubMed:35104454). {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"; 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; 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_000921.5. 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 AlphaFoldDB; Q14432; -. DR EMDB; EMD-23494; -. DR EMDB; EMD-23495; -. DR EMDB; EMD-31103; -. DR EMDB; EMD-31104; -. DR EMDB; EMD-31105; -. DR SMR; Q14432; -. DR BioGRID; 111165; 86. DR CORUM; Q14432; -. DR DIP; DIP-42197N; -. DR FunCoup; Q14432; 1295. DR IntAct; Q14432; 59. DR MINT; Q14432; -. DR NDEx; IQUERY-CP-PDE3A; 3 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000351957; -. DR BindingDB; Q14432; -. DR ChEMBL; CHEMBL241; -. DR DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine. 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; DB16157; Ensifentrine. DR DrugBank; DB05266; Ibudilast. DR DrugBank; DB20144; Imazodan. 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 DrugBank; DB12082; Vesnarinone. DR DrugCentral; Q14432; -. DR GuidetoPHARMACOLOGY; 1298; -. DR GlyGen; Q14432; 7 sites, 1 O-linked glycan (7 sites). DR iPTMnet; Q14432; -. DR PhosphoSitePlus; Q14432; -. DR SwissPalm; Q14432; -. DR BioMuta; PDE3A; -. DR DMDM; 47117888; -. DR jPOST; Q14432; -. DR MassIVE; Q14432; -. DR PaxDb; 9606-ENSP00000351957; -. DR PeptideAtlas; Q14432; -. DR ProteomicsDB; 59987; -. DR Pumba; Q14432; -. DR Antibodypedia; 2869; 258 antibodies from 33 providers. DR DNASU; 5139; -. DR Ensembl; ENST00000359062.4; ENSP00000351957.3; ENSG00000172572.8. 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 AGR; HGNC:8778; -. DR ClinPGx; PA33126; -. DR CTD; 5139; -. DR DisGeNET; 5139; -. DR GeneCards; PDE3A; -. DR HGNC; HGNC:8778; PDE3A. DR HPA; ENSG00000172572; Tissue enhanced (blood vessel, heart muscle). DR MalaCards; PDE3A; -. DR MIM; 112410; phenotype. DR MIM; 123805; gene. DR OpenTargets; ENSG00000172572; -. DR Orphanet; 1276; Brachydactyly-arterial hypertension syndrome. DR VEuPathDB; HostDB:ENSG00000172572; -. DR eggNOG; ENOG502QSV8; Eukaryota. DR GeneTree; ENSGT00940000156628; -. DR HOGENOM; CLU_008844_0_0_1; -. DR InParanoid; Q14432; -. DR OMA; CIPREQI; -. DR OrthoDB; 546632at2759; -. DR PAN-GO; Q14432; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q14432; -. 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 Agora; ENSG00000172572; -. DR BioGRID-ORCS; 5139; 20 hits in 1159 CRISPR screens. DR CD-CODE; F345034F; Signaling cluster. 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 146 other cell types or tissues. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; ISS:UniProtKB. DR GO; GO:0004119; F:3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity; IDA:UniProtKB. 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:0099130; F:estrogen binding; IDA:UniProtKB. DR GO; GO:0030284; F:nuclear estrogen receptor activity; IDA:UniProt. DR GO; GO:0097190; P:apoptotic signaling pathway; 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:0007186; P:G protein-coupled receptor signaling pathway; TAS:Reactome. DR GO; GO:0006629; P:lipid metabolic process; TAS:ProtInc. DR GO; GO:0106072; P:negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0141162; P:negative regulation of cAMP/PKA signal transduction; IBA:GO_Central. DR GO; GO:0043116; P:negative regulation of vascular permeability; IMP:UniProtKB. DR GO; GO:0001556; P:oocyte maturation; IEA:Ensembl. DR GO; GO:0043117; P:positive regulation of vascular permeability; IMP:UniProtKB. DR GO; GO:0060700; P:regulation of ribonuclease activity; IDA:UniProtKB. DR CDD; cd00077; HDc; 1. DR FunFam; 1.10.1300.10:FF:000008; Phosphodiesterase; 1. DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 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 PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1. DR Pfam; PF00233; PDEase_I; 1. DR SMART; SM00471; HDc; 1. DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1. DR PROSITE; PS00126; PDEASE_I_1; 1. DR PROSITE; PS51845; PDEASE_I_2; 1. 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; -. 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; Proteomics identification; KW Reference proteome; Transmembrane; 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..448 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 465..482 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 608..637 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1029..1056 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1100..1113 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1125..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 FT cAMP-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 FT cAMP-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 FT cAMP-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 FT cAMP-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 FT cAMP-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 HELIX 672..674 FT /evidence="ECO:0007829|PDB:7LRC" 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 HELIX 775..777 FT /evidence="ECO:0007829|PDB:7L28" 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 HELIX 984..987 FT /evidence="ECO:0007829|PDB:7L27" FT STRAND 992..994 FT /evidence="ECO:0007829|PDB:7LRC" FT HELIX 997..1004 FT /evidence="ECO:0007829|PDB:7L27" FT HELIX 1005..1009 FT /evidence="ECO:0007829|PDB:7L27" FT HELIX 1010..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 //