PDE4A_MOUSE
ID PDE4A_MOUSE Reviewed; 844 AA.
AC O89084; Q8R078; Q9JHQ4; Q9QX48; Q9QX49; Q9QXI8;
DT 19-SEP-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2002, sequence version 2.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=cAMP-specific 3',5'-cyclic phosphodiesterase 4A;
DE EC=3.1.4.53 {ECO:0000269|PubMed:11267656};
GN Name=Pde4a;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RC TISSUE=Embryonic stem cell;
RX PubMed=10602991; DOI=10.1007/s003350010008;
RA Olsen A.E., Bolger G.B.;
RT "Physical mapping and promoter structure of the murine cAMP-specific
RT phosphodiesterase pde4a gene.";
RL Mamm. Genome 11:41-45(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION (ISOFORM 2), CATALYTIC
RP ACTIVITY (ISOFORM 2), ACTIVITY REGULATION (ISOFORM 2), BIOPHYSICOCHEMICAL
RP PROPERTIES (ISOFORM 2), AND PATHWAY.
RC STRAIN=Swiss Webster; TISSUE=Brain;
RX PubMed=11267656; DOI=10.1016/s0167-4781(01)00164-6;
RA Cherry J.A., Thompson B.E., Pho V.;
RT "Diazepam and rolipram differentially inhibit cyclic AMP-specific
RT phosphodiesterases PDE4A1 and PDE4B3 in the mouse.";
RL Biochim. Biophys. Acta 1518:27-35(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC STRAIN=FVB/N; TISSUE=Salivary gland;
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 248-355 (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=9677330; DOI=10.1042/bj3330693;
RA Sullivan M., Rena G., Begg F., Gordon L., Olsen A.S., Houslay M.D.;
RT "Identification and characterization of the human homologue of the short
RT PDE4A cAMP-specific phosphodiesterase 4A variant RD1 (PDE4A1) by analysis
RT of the human HSPDE4A gene locus located at chromosome 19p13.2.";
RL Biochem. J. 333:693-703(1998).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147 AND SER-333, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Hydrolyzes the second messenger 3',5'-cyclic AMP (cAMP),
CC which is a key regulator of many important physiological processes.
CC {ECO:0000269|PubMed:11267656}.
CC -!- FUNCTION: [Isoform 2]: Efficiently hydrolyzes cAMP.
CC {ECO:0000269|PubMed:11267656}.
CC -!- CATALYTIC ACTIVITY: [Isoform 2]:
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; EC=3.1.4.53;
CC Evidence={ECO:0000269|PubMed:11267656};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25278;
CC Evidence={ECO:0000305|PubMed:11267656};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:P27815};
CC Note=Binds 2 divalent metal cations per subunit. Site 1 may
CC preferentially bind zinc ions. {ECO:0000250|UniProtKB:P27815};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P27815};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:Q07343};
CC Note=Binds 2 divalent metal cations per subunit (By similarity). Site 2
CC has a preference for magnesium and/or manganese ions (By similarity).
CC {ECO:0000250|UniProtKB:P27815, ECO:0000250|UniProtKB:Q07343};
CC -!- ACTIVITY REGULATION: [Isoform 2]: Inhibited by rolipram and diazepam.
CC {ECO:0000269|PubMed:11267656}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=9.2 uM for cAMP {ECO:0000269|PubMed:11267656};
CC Vmax=37.9 nmol/min/mg enzyme toward cAMP
CC {ECO:0000269|PubMed:11267656};
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from
CC 3',5'-cyclic AMP: step 1/1. {ECO:0000305|PubMed:11267656}.
CC -!- SUBUNIT: Interacts with LYN (via SH3 domain). Interacts with ARRB2.
CC {ECO:0000250|UniProtKB:P27815}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P27815}. Membrane; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P27815}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Additional isoforms seem to exist.;
CC Name=1;
CC IsoId=O89084-1; Sequence=Displayed;
CC Name=2; Synonyms=PDE4A1 {ECO:0000303|PubMed:11267656};
CC IsoId=O89084-2; Sequence=VSP_004563, VSP_004564;
CC Name=3;
CC IsoId=O89084-3; Sequence=VSP_004562;
CC -!- PTM: Proteolytically cleaved by CASP3. {ECO:0000250|UniProtKB:P27815}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE4 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH27224.2; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF142646; AAF14519.1; -; Genomic_DNA.
DR EMBL; AF142643; AAF14519.1; JOINED; Genomic_DNA.
DR EMBL; AF142644; AAF14519.1; JOINED; Genomic_DNA.
DR EMBL; AF142645; AAF14519.1; JOINED; Genomic_DNA.
DR EMBL; AF142646; AAF14520.1; -; Genomic_DNA.
DR EMBL; AF142644; AAF14520.1; JOINED; Genomic_DNA.
DR EMBL; AF142645; AAF14520.1; JOINED; Genomic_DNA.
DR EMBL; AF208021; AAF19201.2; -; mRNA.
DR EMBL; AJ297396; CAB96769.1; -; mRNA.
DR EMBL; BC027224; AAH27224.2; ALT_INIT; mRNA.
DR EMBL; U97586; AAC25681.1; -; mRNA.
DR CCDS; CCDS22895.1; -. [O89084-1]
DR CCDS; CCDS22896.1; -. [O89084-2]
DR CCDS; CCDS80964.1; -. [O89084-3]
DR RefSeq; NP_062772.3; NM_019798.5. [O89084-2]
DR RefSeq; NP_899668.1; NM_183408.3. [O89084-1]
DR AlphaFoldDB; O89084; -.
DR SMR; O89084; -.
DR BioGRID; 202078; 4.
DR IntAct; O89084; 2.
DR STRING; 10090.ENSMUSP00000037025; -.
DR BindingDB; O89084; -.
DR ChEMBL; CHEMBL2111373; -.
DR iPTMnet; O89084; -.
DR PhosphoSitePlus; O89084; -.
DR MaxQB; O89084; -.
DR PaxDb; O89084; -.
DR PRIDE; O89084; -.
DR ProteomicsDB; 287806; -. [O89084-1]
DR ProteomicsDB; 287807; -. [O89084-2]
DR ProteomicsDB; 287808; -. [O89084-3]
DR Antibodypedia; 4321; 492 antibodies from 26 providers.
DR DNASU; 18577; -.
DR Ensembl; ENSMUST00000003395; ENSMUSP00000003395; ENSMUSG00000032177. [O89084-2]
DR Ensembl; ENSMUST00000039413; ENSMUSP00000037025; ENSMUSG00000032177. [O89084-1]
DR Ensembl; ENSMUST00000115458; ENSMUSP00000111118; ENSMUSG00000032177. [O89084-3]
DR GeneID; 18577; -.
DR KEGG; mmu:18577; -.
DR UCSC; uc009oki.2; mouse. [O89084-1]
DR UCSC; uc009okl.2; mouse. [O89084-3]
DR UCSC; uc009okm.2; mouse. [O89084-2]
DR CTD; 5141; -.
DR MGI; MGI:99558; Pde4a.
DR VEuPathDB; HostDB:ENSMUSG00000032177; -.
DR eggNOG; KOG3689; Eukaryota.
DR GeneTree; ENSGT00940000159788; -.
DR HOGENOM; CLU_005940_5_0_1; -.
DR InParanoid; O89084; -.
DR OMA; SHCICSF; -.
DR PhylomeDB; O89084; -.
DR TreeFam; TF314638; -.
DR BRENDA; 3.1.4.53; 3474.
DR Reactome; R-MMU-180024; DARPP-32 events.
DR Reactome; R-MMU-418555; G alpha (s) signalling events.
DR UniPathway; UPA00762; UER00747.
DR BioGRID-ORCS; 18577; 5 hits in 74 CRISPR screens.
DR ChiTaRS; Pde4a; mouse.
DR PRO; PR:O89084; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; O89084; protein.
DR Bgee; ENSMUSG00000032177; Expressed in superior frontal gyrus and 143 other tissues.
DR ExpressionAtlas; O89084; baseline and differential.
DR Genevisible; O89084; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0019898; C:extrinsic component of membrane; ISO:MGI.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISO:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; ISO:MGI.
DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IDA:BHF-UCL.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
DR GO; GO:0030552; F:cAMP binding; ISO:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006198; P:cAMP catabolic process; IDA:UniProtKB.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IDA:MGI.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; ISO:MGI.
DR GO; GO:0106070; P:regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:MGI.
DR GO; GO:0010738; P:regulation of protein kinase A signaling; IMP:MGI.
DR GO; GO:0007608; P:sensory perception of smell; IGI:MGI.
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; IPR040844; PDE4_UCR.
DR InterPro; IPR023088; PDEase.
DR InterPro; IPR002073; PDEase_catalytic_dom.
DR InterPro; IPR036971; PDEase_catalytic_dom_sf.
DR InterPro; IPR023174; PDEase_CS.
DR Pfam; PF18100; PDE4_UCR; 1.
DR Pfam; PF00233; PDEase_I; 1.
DR PRINTS; PR00387; PDIESTERASE1.
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; Cytoplasm; Hydrolase; Isopeptide bond;
KW Magnesium; Manganese; Membrane; Metal-binding; Phosphoprotein;
KW Reference proteome; Ubl conjugation; Zinc.
FT CHAIN 1..844
FT /note="cAMP-specific 3',5'-cyclic phosphodiesterase 4A"
FT /id="PRO_0000198807"
FT DOMAIN 343..672
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 1..124
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 819..844
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 49..76
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 82..96
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 419
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 419
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000250|UniProtKB:Q08499"
FT BINDING 419
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 423
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 423
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT BINDING 459
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT BINDING 460
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 460
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT BINDING 460
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 460
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT BINDING 460
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 577
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 577
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT BINDING 628
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000250|UniProtKB:Q08499"
FT BINDING 628
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 631
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000250|UniProtKB:Q08499"
FT BINDING 631
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT SITE 69..70
FT /note="Cleavage; by caspase-3"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT MOD_RES 13
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT MOD_RES 147
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 152
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P54748"
FT MOD_RES 160
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT MOD_RES 204
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT MOD_RES 333
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 672
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT MOD_RES 674
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P27815"
FT CROSSLNK 344
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..234
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11267656,
FT ECO:0000303|PubMed:9677330"
FT /id="VSP_004563"
FT VAR_SEQ 1..102
FT /note="MEPPAAPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPIRIQQRGYSDSA
FT ERSEPERSPHRPIERADAVDTGDRPGLRTTRMSWPSSFHGTGTGGGSSRR -> MRSSA
FT APRARPRPPALALPLGPESLTHFSFSEEDTLRHPPGRCVS (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_004562"
FT VAR_SEQ 235..256
FT /note="WCLEQLETMQTYRSVSEMASHK -> MPLVDFFCETCSKPWLVGWWDQ (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:11267656,
FT ECO:0000303|PubMed:9677330"
FT /id="VSP_004564"
FT CONFLICT 516
FT /note="R -> K (in Ref. 2; AAF19201)"
FT /evidence="ECO:0000305"
FT CONFLICT 685
FT /note="S -> G (in Ref. 3; AAH27224)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 844 AA; 93558 MW; 632396C9F70E0F61 CRC64;
MEPPAAPSER SLSLSLPGPR EGQATLKPPP QHLWRQPRTP IRIQQRGYSD SAERSEPERS
PHRPIERADA VDTGDRPGLR TTRMSWPSSF HGTGTGGGSS RRLEAENGPT PSPGRSPLDS
QASPGLMLHA GAATSQRRES FLYRSDSDYD MSPKTMSRNS SVASEAHGED LIVTPFAQVL
ASLRNVRSNF SLLTNVPIPS NKRSPLGGPP SVCKATLSEE TCQQLARETL EELDWCLEQL
ETMQTYRSVS EMASHKFKRM LNRELTHLSE MSRSGNQVSE YISNTFLDKQ HEVEIPSPTP
RQRPFQQPPP AAVQQAQPMS QITGLKKLVH TGSLNINVPR FGVKTDQEDL LAQELENLSK
WGLNIFCVSE YAGGRSLSCI MYTIFQERDL LKKFHIPVDT MMTYMLTLED HYHADVAYHN
SLHAADVLQS THVLLATPAL DAVFTDLEIL AALFAAAIHD VDHPGVSNQF LINTNSELAL
MYNDESVLEN HHLAVGFKLL QEENCDIFQN LSKRQRQSLR KMVIDMVLAT DMSKHMTLLA
DLKTMVETKK VTSSGVLLLD NYSDRIQVLR NMVHCADLSN PTKPLELYRQ WTDRIMAEFF
QQGDRERERG MEISPMCDKH TASVEKSQVG FIDYIVHPLW ETWADLVHPD AQDILDTLED
NRDWYHSAIR QSPSPTLEEE PGVLSDPALP DKFQFELTLE EEDEEDSLEV PGLPCTEETL
LAPHDTRAQA MEQSKVKGQS PAVVEVAESL KQETASAHGA PEESAEAVGH SFSLETSILP
DLRTLSPSEE AQGLLGLPSM AAEVEAPRDH LAAMRACSAC SGTSGDNSAV ISAPGRWGSG
GDPA
