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cAMP-specific 3',5'-cyclic phosphodiesterase 4A (EC 3.1.4.53) (DPDE2) (PDE46)

 PDE4A_HUMAN             Reviewed;         886 AA.
P27815; O75522; O76092; Q16255; Q16691; Q5DM53; Q6PMT2; Q8IVA7;
Q8WUQ3; Q9H3H2;
01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
17-OCT-2006, sequence version 3.
30-AUG-2017, entry version 168.
RecName: Full=cAMP-specific 3',5'-cyclic phosphodiesterase 4A;
EC=3.1.4.53;
AltName: Full=DPDE2;
AltName: Full=PDE46;
Name=PDE4A; Synonyms=DPDE2;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=8413254; DOI=10.1128/MCB.13.10.6558;
Bolger G., Michaeli T., Martins T., St John T., Steiner B.,
Rodgers L., Riggs M., Wigler M., Ferguson K.;
"A family of human phosphodiesterases homologous to the dunce learning
and memory gene product of Drosophila melanogaster are potential
targets for antidepressant drugs.";
Mol. Cell. Biol. 13:6558-6571(1993).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
PubMed=7888306; DOI=10.1016/0898-6568(94)00039-5;
Sullivan M., Egerton M., Shakur Y., Marquardsen A., Houslay M.D.;
"Molecular cloning and expression, in both COS-1 cells and S.
cerevisiae, of a human cytosolic type-IVA, cyclic AMP specific
phosphodiesterase (hPDE-IVA-h6.1).";
Cell. Signal. 6:793-812(1994).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 5), AND VARIANT GLU-736.
PubMed=7772058; DOI=10.1042/bj3080683;
Horton Y.M., Sullivan M., Houslay M.D.;
"Molecular cloning of a novel splice variant of human type IVA (PDE-
IVA) cyclic AMP phosphodiesterase and localization of the gene to the
p13.2-q12 region of human chromosome 19.";
Biochem. J. 308:683-691(1995).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2; 3; 4 AND 5).
TISSUE=Brain;
PubMed=9677330; DOI=10.1042/bj3330693;
Sullivan M., Rena G., Begg F., Gordon L., Olsen A.S., Houslay M.D.;
"Identification and characterization of the human homologue of the
short PDE4A cAMP-specific phosphodiesterase 4A variant RD1 (PDE4A1) by
analysis of the human HSPDE4A gene locus located at chromosome
19p13.2.";
Biochem. J. 333:693-703(1998).
[5]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6), SUBCELLULAR LOCATION,
BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, TISSUE SPECIFICITY,
AND INTERACTION WITH LYN.
TISSUE=Brain;
PubMed=11306681;
Rena G., Begg F., Ross A., MacKenzie C., McPhee I., Campbell L.,
Huston E., Sullivan M., Houslay M.D.;
"Molecular cloning, genomic positioning, promoter identification, and
characterization of the novel cyclic AMP-specific phosphodiesterase
PDE4A10.";
Mol. Pharmacol. 59:996-1011(2001).
[6]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, TISSUE
SPECIFICITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES,
PHOSPHORYLATION AT SER-119 (ISOFORM 2), CLEAVAGE BY CASPASE-3 (ISOFORM
1), AND INTERACTION WITH LYN AND ARRB2.
PubMed=15738310; DOI=10.1124/mol.104.009423;
Wallace D.A., Johnston L.A., Huston E., Macmaster D., Houslay T.M.,
Cheung Y.-F., Campbell L., Millen J.E., Smith R.A., Gall I.,
Knowles R.G., Sullivan M., Houslay M.D.;
"Identification and characterization of PDE4A11, a novel, widely
expressed long isoform encoded by the human PDE4A cAMP
phosphodiesterase gene.";
Mol. Pharmacol. 67:1920-1934(2005).
[7]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), SUBCELLULAR LOCATION, ENZYME
REGULATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION AT SER-123
(ISOFORM 7).
PubMed=18095939; DOI=10.1042/BJ20071251;
Mackenzie K.F., Topping E.C., Bugaj-Gaweda B., Deng C., Cheung Y.-F.,
Olsen A.E., Stockard C.R., High Mitchell L., Baillie G.S.,
Grizzle W.E., De Vivo M., Houslay M.D., Wang D., Bolger G.B.;
"Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific
phosphodiesterase that has undergone rapid evolutionary change.";
Biochem. J. 411:361-369(2008).
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15057824; DOI=10.1038/nature02399;
Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
Rubin E.M., Lucas S.M.;
"The DNA sequence and biology of human chromosome 19.";
Nature 428:529-535(2004).
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[10]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
TISSUE=Brain;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[11]
NUCLEOTIDE SEQUENCE [MRNA] OF 112-886, AND VARIANT GLU-736.
TISSUE=Monocyte;
PubMed=2160582; DOI=10.1128/MCB.10.6.2678;
Livi G.P., Kmetz P., McHale M.M., Cieslinski L.B., Sathe G.M.,
Taylor D.P., Davis R.L., Torphy T.J., Balcarek J.M.;
"Cloning and expression of cDNA for a human low-Km, rolipram-sensitive
cyclic AMP phosphodiesterase.";
Mol. Cell. Biol. 10:2678-2686(1990).
[12]
SEQUENCE REVISION.
McLaughlin M.M.;
Submitted (JAN-1991) to the EMBL/GenBank/DDBJ databases.
[13]
FUNCTION, PHOSPHORYLATION AT SER-686 AND SER-688, PHOSPHORYLATION AT
SER-119 (ISOFORM 2), PHOSPHORYLATION AT SER-123 (ISOFORM 7), AND
IDENTIFICATION BY MASS SPECTROMETRY.
PubMed=11566027; DOI=10.1006/abbi.2001.2513;
Lario P.I., Bobechko B., Bateman K., Kelly J., Vrielink A., Huang Z.;
"Purification and characterization of the human pde4a catalytic domain
(pde4a(330-723)) expressed in sf9 cells.";
Arch. Biochem. Biophys. 394:54-60(2001).
[14]
SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
Hillman R.T., Green R.E., Brenner S.E.;
"An unappreciated role for RNA surveillance.";
Genome Biol. 5:R8.1-R8.16(2004).
[15]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[16]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-165, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[17]
SUMOYLATION AT LYS-358 BY PIAS4.
PubMed=20196770; DOI=10.1042/BJ20091672;
Li X., Vadrevu S., Dunlop A., Day J., Advant N., Troeger J.,
Klussmann E., Jaffrey E., Hay R.T., Adams D.R., Houslay M.D.,
Baillie G.S.;
"Selective SUMO modification of cAMP-specific phosphodiesterase-4D5
(PDE4D5) regulates the functional consequences of phosphorylation by
PKA and ERK.";
Biochem. J. 428:55-65(2010).
[18]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-13; SER-209 AND SER-346,
AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[19]
X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 351-683 IN COMPLEX WITH
METAL IONS AND THE INHIBITOR NVP, FUNCTION, AND COFACTOR.
PubMed=17727341; DOI=10.1042/BJ20070970;
Wang H., Peng M.-S., Chen Y., Geng J., Robinson H., Houslay M.D.,
Cai J., Ke H.;
"Structures of the four subfamilies of phosphodiesterase-4 provide
insight into the selectivity of their inhibitors.";
Biochem. J. 408:193-201(2007).
[20]
X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 351-683 IN COMPLEX WITH
METAL IONS AND INHIBITOR.
Cheng R.K.Y., Crawley L., Barker J., Wood M., Felicetti B.,
Whittaker M.;
"Crystal structure of human PDE4a with 4-(3-butoxy-4-
methoxyphenyl)methyl-2-imidazolidone.";
Submitted (JUL-2009) to the PDB data bank.
-!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key
regulator of many important physiological processes.
{ECO:0000269|PubMed:11566027, ECO:0000269|PubMed:17727341}.
-!- CATALYTIC ACTIVITY: Adenosine 3',5'-cyclic phosphate + H(2)O =
adenosine 5'-phosphate.
-!- COFACTOR:
Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
Evidence={ECO:0000269|PubMed:17727341};
Note=Binds 2 divalent metal cations per subunit. Site 1 may
preferentially bind zinc ions, while site 2 has a preference for
magnesium and/or manganese ions. {ECO:0000269|PubMed:17727341};
-!- ENZYME REGULATION: Isoform 1, isoform 2, isoform 6 and isoform 7
are inhibited by rolipram and cilomilast. Isoform 1, isoform 2 and
isoform 6 are inhibited by 4-[(3-butoxy-4-methoxyphenyl)-methyl]-
2-imidazolidinone (Ro 20-1724), roflumilast and denbufylline.
{ECO:0000269|PubMed:11306681, ECO:0000269|PubMed:15738310,
ECO:0000269|PubMed:18095939}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
KM=4.0 uM for cAMP (isoform 2) {ECO:0000269|PubMed:11306681,
ECO:0000269|PubMed:15738310};
KM=3 uM for cAMP (isoform 6) {ECO:0000269|PubMed:11306681,
ECO:0000269|PubMed:15738310};
-!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from
3',5'-cyclic AMP: step 1/1.
-!- SUBUNIT: Isoform 1 interacts with LYN. Isoform 2 and isoform 6
interact weakly with LYN. Isoform 1, isoform 2 and isoform 6
interact with ARRB2. {ECO:0000269|PubMed:11306681,
ECO:0000269|PubMed:15738310, ECO:0000269|PubMed:17727341,
ECO:0000269|Ref.20}.
-!- SUBCELLULAR LOCATION: Isoform 1: Cytoplasm, perinuclear region.
-!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm, perinuclear region.
Cell projection, ruffle membrane.
-!- SUBCELLULAR LOCATION: Isoform 4: Membrane; Peripheral membrane
protein. Note=Isoform 4 has propensity for association with
membranes.
-!- SUBCELLULAR LOCATION: Isoform 6: Cytoplasm, perinuclear region.
-!- SUBCELLULAR LOCATION: Isoform 7: Cytoplasm. Membrane.
Note=Predominantly cytoplasmic.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=7;
Comment=Additional isoforms seem to exist.;
Name=1; Synonyms=PDE4A4, PDE4A4B, PDE46;
IsoId=P27815-1; Sequence=Displayed;
Name=2; Synonyms=TM3, PDE4A11;
IsoId=P27815-2; Sequence=VSP_004556;
Note=Contains a phosphoserine at position 119.
{ECO:0000269|PubMed:11566027};
Name=3; Synonyms=PDE4A7, PDE4A6;
IsoId=P27815-3; Sequence=VSP_004557;
Name=4; Synonyms=PDE4A1, RD1;
IsoId=P27815-4; Sequence=VSP_004558;
Name=5; Synonyms=PDE4A8A, 2EL;
IsoId=P27815-5; Sequence=VSP_004559, VSP_004560, VSP_004561;
Note=May be produced at very low levels due to a premature stop
codon in the mRNA, leading to nonsense-mediated mRNA decay.
Probably represents a non-functional splice isoform.;
Name=6; Synonyms=PDE4A10;
IsoId=P27815-6; Sequence=VSP_038185;
Name=7; Synonyms=PDE4A8;
IsoId=P27815-7; Sequence=VSP_038186;
Note=Contains a phosphoserine at position 123.
{ECO:0000269|PubMed:11566027};
-!- TISSUE SPECIFICITY: Isoform 1 is widely expressed. Isoform 2 is
abundant in liver, stomach, testis, thyroid and adrenal glands. It
is also found in placenta, kidney, pancreas, ovary, uterus, skin,
monocytes, mast cells, macrophages, as well as in bronchial smooth
muscle. Isoform 6 is expressed at high levels in the heart and
small intestine. It is also found in the brain, kidney, spleen,
colon, salivary gland, ovary and peripheral blood lymphocytes.
Isoform 7 is expressed predominantly in skeletal muscle and brain
and at lower levels in the testis. Isoform 7 is expressed in the
brain. Found in specific neuronal subpopulations in cortex, spinal
cord and cerebellum (at protein level).
{ECO:0000269|PubMed:11306681, ECO:0000269|PubMed:15738310,
ECO:0000269|PubMed:18095939}.
-!- PTM: Phosphorylation by MAPKAPK2 its activation through PKA
phosphorylation (By similarity). Phosphorylated at Ser-686 and
Ser-688 when expressed in S.frugiperda cells. Isoform 2 and
isoform 7 are activated by phosphorylation at Ser-119 and Ser-123
respectively by PKA. {ECO:0000250, ECO:0000269|PubMed:11566027}.
-!- PTM: Proteolytically cleaved by caspase-3.
-!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase
family. PDE4 subfamily. {ECO:0000305}.
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EMBL; L20965; AAA03588.1; -; mRNA.
EMBL; S75213; AAB33798.1; -; mRNA.
EMBL; U18087; AAC50458.1; -; mRNA.
EMBL; U18088; AAA98540.1; -; mRNA.
EMBL; AF069491; AAC35012.1; -; Genomic_DNA.
EMBL; AF069487; AAC35012.1; JOINED; Genomic_DNA.
EMBL; AF069489; AAC35012.1; JOINED; Genomic_DNA.
EMBL; AF069490; AAC35012.1; JOINED; Genomic_DNA.
EMBL; AF069491; AAC35013.1; -; Genomic_DNA.
EMBL; AF069489; AAC35013.1; JOINED; Genomic_DNA.
EMBL; AF069490; AAC35013.1; JOINED; Genomic_DNA.
EMBL; AF069491; AAC35014.1; -; Genomic_DNA.
EMBL; AF069489; AAC35014.1; JOINED; Genomic_DNA.
EMBL; AF069490; AAC35014.1; JOINED; Genomic_DNA.
EMBL; AF069491; AAC35015.1; -; Genomic_DNA.
EMBL; AF069488; AAC35015.1; JOINED; Genomic_DNA.
EMBL; AF069489; AAC35015.1; JOINED; Genomic_DNA.
EMBL; AF069490; AAC35015.1; JOINED; Genomic_DNA.
EMBL; U68532; AAC63832.1; -; mRNA.
EMBL; U97584; AAC25679.1; -; mRNA.
EMBL; AF073745; AAD34217.2; -; mRNA.
EMBL; AY618547; AAU82096.1; -; mRNA.
EMBL; AY593872; AAT00628.1; -; mRNA.
EMBL; AC011548; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC011529; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC011461; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CH471106; EAW84104.1; -; Genomic_DNA.
EMBL; CH471106; EAW84105.1; -; Genomic_DNA.
EMBL; CH471106; EAW84108.1; -; Genomic_DNA.
EMBL; BC019864; AAH19864.1; -; mRNA.
EMBL; BC038234; AAH38234.1; -; mRNA.
EMBL; M37744; AAA69697.1; -; mRNA.
CCDS; CCDS12238.1; -. [P27815-4]
CCDS; CCDS45961.1; -. [P27815-1]
CCDS; CCDS45962.1; -. [P27815-2]
CCDS; CCDS45963.1; -. [P27815-6]
CCDS; CCDS58649.1; -. [P27815-7]
PIR; A54442; A54442.
PIR; S55348; S55348.
RefSeq; NP_001104777.1; NM_001111307.1. [P27815-1]
RefSeq; NP_001104778.1; NM_001111308.1. [P27815-2]
RefSeq; NP_001104779.1; NM_001111309.1. [P27815-6]
RefSeq; NP_001230050.1; NM_001243121.1. [P27815-7]
RefSeq; NP_006193.1; NM_006202.2. [P27815-4]
RefSeq; XP_011526356.1; XM_011528054.1. [P27815-7]
UniGene; Hs.89901; -.
PDB; 2QYK; X-ray; 2.10 A; A/B=351-683.
PDB; 3I8V; X-ray; 2.25 A; A/B=351-683.
PDB; 3TVX; X-ray; 2.84 A; A/B=351-683.
PDBsum; 2QYK; -.
PDBsum; 3I8V; -.
PDBsum; 3TVX; -.
ProteinModelPortal; P27815; -.
SMR; P27815; -.
BioGrid; 111167; 7.
IntAct; P27815; 4.
STRING; 9606.ENSP00000270474; -.
BindingDB; P27815; -.
ChEMBL; CHEMBL254; -.
DrugBank; DB06842; (4R)-4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one.
DrugBank; DB05676; Apremilast.
DrugBank; DB00201; Caffeine.
DrugBank; DB05219; Crisaborole.
DrugBank; DB00975; Dipyridamole.
DrugBank; DB06751; Drotaverine.
DrugBank; DB00651; Dyphylline.
DrugBank; DB00824; Enprofylline.
DrugBank; DB05266; Ibudilast.
DrugBank; DB01088; Iloprost.
DrugBank; DB01303; Oxtriphylline.
DrugBank; DB05876; PDE4.
DrugBank; DB00806; Pentoxifylline.
DrugBank; DB01791; Piclamilast.
DrugBank; DB01656; Roflumilast.
DrugBank; DB00277; Theophylline.
DrugBank; DB08811; Tofisopam.
GuidetoPHARMACOLOGY; 1300; -.
iPTMnet; P27815; -.
PhosphoSitePlus; P27815; -.
BioMuta; PDE4A; -.
DMDM; 116242706; -.
EPD; P27815; -.
MaxQB; P27815; -.
PaxDb; P27815; -.
PeptideAtlas; P27815; -.
PRIDE; P27815; -.
DNASU; 5141; -.
Ensembl; ENST00000293683; ENSP00000293683; ENSG00000065989. [P27815-2]
Ensembl; ENST00000344979; ENSP00000341007; ENSG00000065989. [P27815-4]
Ensembl; ENST00000380702; ENSP00000370078; ENSG00000065989. [P27815-1]
Ensembl; ENST00000440014; ENSP00000394754; ENSG00000065989. [P27815-6]
Ensembl; ENST00000592685; ENSP00000468507; ENSG00000065989. [P27815-7]
GeneID; 5141; -.
KEGG; hsa:5141; -.
UCSC; uc002moj.3; human. [P27815-1]
CTD; 5141; -.
DisGeNET; 5141; -.
GeneCards; PDE4A; -.
HGNC; HGNC:8780; PDE4A.
HPA; CAB017632; -.
HPA; HPA043310; -.
HPA; HPA076091; -.
MIM; 600126; gene.
neXtProt; NX_P27815; -.
OpenTargets; ENSG00000065989; -.
PharmGKB; PA33128; -.
eggNOG; KOG3689; Eukaryota.
eggNOG; ENOG410XRI7; LUCA.
GeneTree; ENSGT00760000118889; -.
HOVERGEN; HBG108239; -.
KO; K13293; -.
OMA; GPQFQPM; -.
OrthoDB; EOG091G06CD; -.
PhylomeDB; P27815; -.
TreeFam; TF314638; -.
BRENDA; 3.1.4.17; 2681.
BRENDA; 3.1.4.53; 2681.
Reactome; R-HSA-180024; DARPP-32 events.
Reactome; R-HSA-418555; G alpha (s) signalling events.
UniPathway; UPA00762; UER00747.
ChiTaRS; PDE4A; human.
EvolutionaryTrace; P27815; -.
GeneWiki; PDE4A; -.
GenomeRNAi; 5141; -.
PRO; PR:P27815; -.
Proteomes; UP000005640; Chromosome 19.
Bgee; ENSG00000065989; -.
CleanEx; HS_PDE4A; -.
ExpressionAtlas; P27815; baseline and differential.
Genevisible; P27815; HS.
GO; GO:0005829; C:cytosol; TAS:Reactome.
GO; GO:0016020; C:membrane; TAS:ProtInc.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
GO; GO:0005886; C:plasma membrane; IDA:HPA.
GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IDA:BHF-UCL.
GO; GO:0030552; F:cAMP binding; IGI:BHF-UCL.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0006198; P:cAMP catabolic process; IDA:BHF-UCL.
GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
GO; GO:0043949; P:regulation of cAMP-mediated signaling; IEA:Ensembl.
GO; GO:0010738; P:regulation of protein kinase A signaling; IEA:Ensembl.
GO; GO:0007608; P:sensory perception of smell; IEA:Ensembl.
GO; GO:0007165; P:signal transduction; TAS:ProtInc.
Gene3D; 1.10.1300.10; -; 1.
InterPro; IPR003607; HD/PDEase_dom.
InterPro; IPR023088; PDEase.
InterPro; IPR002073; PDEase_catalytic_dom.
InterPro; IPR023174; PDEase_CS.
Pfam; PF00233; PDEase_I; 1.
PRINTS; PR00387; PDIESTERASE1.
SMART; SM00471; HDc; 1.
PROSITE; PS00126; PDEASE_I; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; cAMP; Cell membrane;
Cell projection; Complete proteome; Cytoplasm; Hydrolase;
Isopeptide bond; Membrane; Metal-binding; Phosphoprotein;
Polymorphism; Reference proteome; Ubl conjugation.
CHAIN 1 886 cAMP-specific 3',5'-cyclic
phosphodiesterase 4A.
/FTId=PRO_0000198806.
NP_BIND 433 437 cAMP. {ECO:0000250}.
REGION 330 723 Catalytic.
ACT_SITE 433 433 Proton donor. {ECO:0000250}.
METAL 437 437 Divalent metal cation 1.
METAL 473 473 Divalent metal cation 1.
METAL 474 474 Divalent metal cation 1.
METAL 474 474 Divalent metal cation 2.
METAL 591 591 Divalent metal cation 1.
BINDING 474 474 cAMP. {ECO:0000250}.
BINDING 591 591 cAMP. {ECO:0000250}.
BINDING 642 642 cAMP. {ECO:0000250}.
SITE 69 70 Cleavage; by caspase-3.
SITE 594 594 Binds AMP, but not cAMP. {ECO:0000250}.
MOD_RES 13 13 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 152 152 Phosphoserine; by MAPKAPK2.
{ECO:0000250|UniProtKB:P54748}.
MOD_RES 157 157 Phosphoserine.
{ECO:0000250|UniProtKB:P54748}.
MOD_RES 165 165 Phosphoserine.
{ECO:0000244|PubMed:19690332}.
MOD_RES 209 209 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 346 346 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 686 686 Phosphoserine.
{ECO:0000305|PubMed:11566027}.
MOD_RES 688 688 Phosphoserine.
{ECO:0000305|PubMed:11566027}.
CROSSLNK 358 358 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO).
{ECO:0000269|PubMed:20196770}.
VAR_SEQ 1 367 MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPI
RIQQRGYSDSAERAERERQPHRPIERADAMDTSDRPGLRTT
RMSWPSSFHGTGTGSGGAGGGSSRRFEAENGPTPSPGRSPL
DSQASPGLVLHAGAATSQRRESFLYRSDSDYDMSPKTMSRN
SSVTSEAHAEDLIVTPFAQVLASLRSVRSNFSLLTNVPVPS
NKRSPLGGPTPVCKATLSEETCQQLARETLEELDWCLEQLE
TMQTYRSVSEMASHKFKRMLNRELTHLSEMSRSGNQVSEYI
STTFLDKQNEVEIPSPTMKEREKQQAPRPRPSQPPPPPVPH
LQPMSQITGLKKLMHSNSLNNSNIPRFGVKTDQEELLAQ
-> MVLPSDQGFKLLGNVLQGPEPYRLLTSGLRLHQ (in
isoform 5). {ECO:0000303|PubMed:7772058,
ECO:0000303|PubMed:9677330}.
/FTId=VSP_004559.
VAR_SEQ 1 261 MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPI
RIQQRGYSDSAERAERERQPHRPIERADAMDTSDRPGLRTT
RMSWPSSFHGTGTGSGGAGGGSSRRFEAENGPTPSPGRSPL
DSQASPGLVLHAGAATSQRRESFLYRSDSDYDMSPKTMSRN
SSVTSEAHAEDLIVTPFAQVLASLRSVRSNFSLLTNVPVPS
NKRSPLGGPTPVCKATLSEETCQQLARETLEELDWCLEQLE
TMQTYRSVSEMASHK -> MPLVDFFCETCSKPWLVGWWDQ
(in isoform 4).
{ECO:0000303|PubMed:15489334,
ECO:0000303|PubMed:9677330}.
/FTId=VSP_004558.
VAR_SEQ 1 209 MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPI
RIQQRGYSDSAERAERERQPHRPIERADAMDTSDRPGLRTT
RMSWPSSFHGTGTGSGGAGGGSSRRFEAENGPTPSPGRSPL
DSQASPGLVLHAGAATSQRRESFLYRSDSDYDMSPKTMSRN
SSVTSEAHAEDLIVTPFAQVLASLRSVRSNFSLLTNVPVPS
NKRS -> MCPFPVTTV (in isoform 3).
{ECO:0000303|PubMed:7772058,
ECO:0000303|PubMed:7888306,
ECO:0000303|PubMed:9677330}.
/FTId=VSP_004557.
VAR_SEQ 1 107 MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPI
RIQQRGYSDSAERAERERQPHRPIERADAMDTSDRPGLRTT
RMSWPSSFHGTGTGSGGAGGGSSRR -> MARPRGLGRIPE
LQLVAFPVAVAAEDEAFLPEPLAPRAPRRPRSPPSSPVFFA
SPSPTFRRRLRLLRSCQDLGRQAWAGAG (in isoform
2). {ECO:0000303|PubMed:15738310,
ECO:0000303|PubMed:9677330}.
/FTId=VSP_004556.
VAR_SEQ 1 107 MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPI
RIQQRGYSDSAERAERERQPHRPIERADAMDTSDRPGLRTT
RMSWPSSFHGTGTGSGGAGGGSSRR -> MRSGAAPRARPR
PPALALPPTGPESLTHFPFSDEDTRRHPPGRSVS (in
isoform 6).
{ECO:0000303|PubMed:11306681}.
/FTId=VSP_038185.
VAR_SEQ 1 107 MEPPTVPSERSLSLSLPGPREGQATLKPPPQHLWRQPRTPI
RIQQRGYSDSAERAERERQPHRPIERADAMDTSDRPGLRTT
RMSWPSSFHGTGTGSGGAGGGSSRR -> MKRSRSALSVAG
TGDERSRETPESDRANMLGADLRRPRRRLSSGPGLGWAQPE
PSDPGVPLPPRPTTLPLLIPPRISITRAENDS (in
isoform 7).
{ECO:0000303|PubMed:18095939}.
/FTId=VSP_038186.
VAR_SEQ 644 657 GFIDYIVHPLWETW -> QARGIDGRAQGGFY (in
isoform 5). {ECO:0000303|PubMed:7772058,
ECO:0000303|PubMed:9677330}.
/FTId=VSP_004560.
VAR_SEQ 658 886 Missing (in isoform 5).
{ECO:0000303|PubMed:7772058,
ECO:0000303|PubMed:9677330}.
/FTId=VSP_004561.
VARIANT 736 736 A -> E (in dbSNP:rs1051738).
{ECO:0000269|PubMed:2160582,
ECO:0000269|PubMed:7772058}.
/FTId=VAR_059544.
VARIANT 808 808 H -> Y (in dbSNP:rs2230190).
/FTId=VAR_059545.
HELIX 362 368 {ECO:0000244|PDB:2QYK}.
HELIX 369 371 {ECO:0000244|PDB:2QYK}.
HELIX 379 385 {ECO:0000244|PDB:2QYK}.
TURN 386 388 {ECO:0000244|PDB:2QYK}.
HELIX 390 401 {ECO:0000244|PDB:2QYK}.
HELIX 404 407 {ECO:0000244|PDB:2QYK}.
HELIX 412 424 {ECO:0000244|PDB:2QYK}.
STRAND 430 434 {ECO:0000244|PDB:2QYK}.
HELIX 435 449 {ECO:0000244|PDB:2QYK}.
HELIX 452 454 {ECO:0000244|PDB:2QYK}.
TURN 455 457 {ECO:0000244|PDB:2QYK}.
HELIX 460 472 {ECO:0000244|PDB:2QYK}.
TURN 473 476 {ECO:0000244|PDB:2QYK}.
HELIX 482 487 {ECO:0000244|PDB:2QYK}.
HELIX 491 495 {ECO:0000244|PDB:2QYK}.
TURN 496 498 {ECO:0000244|PDB:2QYK}.
HELIX 501 512 {ECO:0000244|PDB:2QYK}.
HELIX 513 515 {ECO:0000244|PDB:2QYK}.
TURN 521 524 {ECO:0000244|PDB:2QYK}.
HELIX 527 542 {ECO:0000244|PDB:2QYK}.
HELIX 546 548 {ECO:0000244|PDB:2QYK}.
HELIX 549 561 {ECO:0000244|PDB:2QYK}.
STRAND 567 569 {ECO:0000244|PDB:2QYK}.
HELIX 576 591 {ECO:0000244|PDB:2QYK}.
HELIX 594 596 {ECO:0000244|PDB:2QYK}.
HELIX 599 622 {ECO:0000244|PDB:2QYK}.
TURN 633 635 {ECO:0000244|PDB:2QYK}.
HELIX 638 648 {ECO:0000244|PDB:2QYK}.
HELIX 650 660 {ECO:0000244|PDB:2QYK}.
TURN 661 665 {ECO:0000244|PDB:2QYK}.
HELIX 666 682 {ECO:0000244|PDB:2QYK}.
SEQUENCE 886 AA; 98143 MW; 92BB9B98BED711E7 CRC64;
MEPPTVPSER SLSLSLPGPR EGQATLKPPP QHLWRQPRTP IRIQQRGYSD SAERAERERQ
PHRPIERADA MDTSDRPGLR TTRMSWPSSF HGTGTGSGGA GGGSSRRFEA ENGPTPSPGR
SPLDSQASPG LVLHAGAATS QRRESFLYRS DSDYDMSPKT MSRNSSVTSE AHAEDLIVTP
FAQVLASLRS VRSNFSLLTN VPVPSNKRSP LGGPTPVCKA TLSEETCQQL ARETLEELDW
CLEQLETMQT YRSVSEMASH KFKRMLNREL THLSEMSRSG NQVSEYISTT FLDKQNEVEI
PSPTMKEREK QQAPRPRPSQ PPPPPVPHLQ PMSQITGLKK LMHSNSLNNS NIPRFGVKTD
QEELLAQELE NLNKWGLNIF CVSDYAGGRS LTCIMYMIFQ ERDLLKKFRI PVDTMVTYML
TLEDHYHADV AYHNSLHAAD VLQSTHVLLA TPALDAVFTD LEILAALFAA AIHDVDHPGV
SNQFLINTNS ELALMYNDES VLENHHLAVG FKLLQEDNCD IFQNLSKRQR QSLRKMVIDM
VLATDMSKHM TLLADLKTMV ETKKVTSSGV LLLDNYSDRI QVLRNMVHCA DLSNPTKPLE
LYRQWTDRIM AEFFQQGDRE RERGMEISPM CDKHTASVEK SQVGFIDYIV HPLWETWADL
VHPDAQEILD TLEDNRDWYY SAIRQSPSPP PEEESRGPGH PPLPDKFQFE LTLEEEEEEE
ISMAQIPCTA QEALTAQGLS GVEEALDATI AWEASPAQES LEVMAQEASL EAELEAVYLT
QQAQSTGSAP VAPDEFSSRE EFVVAVSHSS PSALALQSPL LPAWRTLSVS EHAPGLPGLP
STAAEVEAQR EHQAAKRACS ACAGTFGEDT SALPAPGGGG SGGDPT


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