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cAMP-specific 3',5'-cyclic phosphodiesterase 4D (EC 3.1.4.53) (DPDE3) (PDE43)

 PDE4D_HUMAN             Reviewed;         809 AA.
Q08499; O43433; Q13549; Q13550; Q13551; Q7Z2L8; Q8IV84; Q8IVA9;
Q8IVD2; Q8IVD3; Q96HL4; Q9HCX7;
01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
01-DEC-2000, sequence version 2.
22-NOV-2017, entry version 193.
RecName: Full=cAMP-specific 3',5'-cyclic phosphodiesterase 4D;
EC=3.1.4.53;
AltName: Full=DPDE3;
AltName: Full=PDE43;
Name=PDE4D; Synonyms=DPDE3;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4).
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] (ISOFORMS 1; 2 AND 4).
PubMed=8797812; DOI=10.1016/0014-5793(96)00300-6;
Nemoz G., Zhang R.B., Sette C., Conti M.;
"Identification of cyclic AMP-phosphodiesterase variants from the
PDE4D gene expressed in human peripheral mononuclear cells.";
FEBS Lett. 384:97-102(1996).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 10).
TISSUE=Heart;
PubMed=8125310; DOI=10.1016/0378-1119(94)90818-4;
Baecker P.A., Obernolte R., Bach C., Yee C., Shelton E.R.;
"Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP
phosphodiesterase (PDE IVD).";
Gene 138:253-256(1994).
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4; 5 AND 10), AND
SEQUENCE REVISION (ISOFORM 1).
PubMed=9371713; DOI=10.1042/bj3280539;
Bolger G.B., Erdogan S., Jones R.E., Loughney K., Scotland G.,
Hoffmann R., Wilkinson I., Farrell C., Houslay M.D.;
"Characterization of five different proteins produced by alternatively
spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D
gene.";
Biochem. J. 328:539-548(1997).
[5]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM N3), AND ALTERNATIVE SPLICING.
TISSUE=Umbilical vein endothelial cell;
PubMed=10913353; DOI=10.1006/bbrc.2000.3146;
Miro X., Casacuberta J.M., Gutierrez-Lopez M.D., Landazuri M.O.,
Puigdomenech P.;
"Phosphodiesterases 4D and 7A splice variants in the response of HUVEC
cells to TNF-alpha1.";
Biochem. Biophys. Res. Commun. 274:415-421(2000).
[6]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 6; 7; 8 AND 9), PHOSPHORYLATION,
AND TISSUE SPECIFICITY.
PubMed=12834813; DOI=10.1016/S0898-6568(03)00042-1;
Wang D., Deng C., Bugaj-Gaweda B., Kwan M., Gunwaldsen C., Leonard C.,
Xin X., Hu Y., Unterbeck A., De Vivo M.;
"Cloning and characterization of novel PDE4D isoforms PDE4D6 and
PDE4D7.";
Cell. Signal. 15:883-891(2003).
[7]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 7 AND 9), AND INVOLVEMENT IN
SUSCEPTIBILITY TO STROKE.
PubMed=14517540; DOI=10.1038/ng1245;
Gretarsdottir S., Thorleifsson G., Reynisdottir S.T., Manolescu A.,
Jonsdottir S., Jonsdottir T., Gudmundsdottir T., Bjarnadottir S.M.,
Einarsson O.B., Gudjonsdottir H.M., Hawkins M., Gudmundsson G.,
Gudmundsdottir H., Andrason H., Gudmundsdottir A.S.,
Sigurdardottir M., Chou T.T., Nahmias J., Goss S.,
Sveinbjoernsdottir S., Valdimarsson E.M., Jakobsson F., Agnarsson U.,
Gudnason V., Thorgeirsson G., Fingerle J., Gurney M., Gudbjartsson D.,
Frigge M.L., Kong A., Stefansson K., Gulcher J.R.;
"The gene encoding phosphodiesterase 4D confers risk of ischemic
stroke.";
Nat. Genet. 35:131-138(2003).
[8]
ERRATUM.
Gretarsdottir S., Thorleifsson G., Reynisdottir S.T., Manolescu A.,
Jonsdottir S., Jonsdottir T., Gudmundsdottir T., Bjarnadottir S.M.,
Einarsson O.B., Gudjonsdottir H.M., Hawkins M., Gudmundsson G.,
Gudmundsdottir H., Andrason H., Gudmundsdottir A.S.,
Sigurdardottir M., Chou T.T., Nahmias J., Goss S.,
Sveinbjoernsdottir S., Valdimarsson E.M., Jakobsson F., Agnarsson U.,
Gudnason V., Thorgeirsson G., Fingerle J., Gurney M., Gudbjartsson D.,
Frigge M.L., Kong A., Stefansson K., Gulcher J.R.;
Nat. Genet. 37:555-555(2005).
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 12).
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
Phelan M., Farmer A.;
"Cloning of human full-length CDSs in BD Creator(TM) system donor
vector.";
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
[10]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 6 AND 12).
TISSUE=Brain, and Testis;
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]
INTERACTION WITH RACK1.
PubMed=12193273; DOI=10.1186/1471-2091-3-24;
Bolger G.B., McCahill A., Yarwood S.J., Steele M.S., Warwicker J.,
Houslay M.D.;
"Delineation of RAID1, the RACK1 interaction domain located within the
unique N-terminal region of the cAMP-specific phosphodiesterase,
PDE4D5.";
BMC Biochem. 3:24-24(2002).
[12]
INTERACTION WITH ARRB2, AND SUBCELLULAR LOCATION.
PubMed=14500724; DOI=10.1074/jbc.M303772200;
Bolger G.B., McCahill A., Huston E., Cheung Y.F., McSorley T.,
Baillie G.S., Houslay M.D.;
"The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase
isoform confers preferential interaction with beta-arrestins.";
J. Biol. Chem. 278:49230-49238(2003).
[13]
HOMODIMERIZATION OF LONG ISOFORMS, ENZYME REGULATION BY ROLIPRAM AND
PHOSPHATIDIC ACID, AND PHOSPHORYLATION AT SER-53 (ISOFORM 3).
PubMed=15131123; DOI=10.1074/jbc.M312687200;
Richter W., Conti M.;
"The oligomerization state determines regulatory properties and
inhibitor sensitivity of type 4 cAMP-specific phosphodiesterases.";
J. Biol. Chem. 279:30338-30348(2004).
[14]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
Mann M.;
"Global, in vivo, and site-specific phosphorylation dynamics in
signaling networks.";
Cell 127:635-648(2006).
[15]
DISCUSSION OF INVOLVEMENT IN STROKE.
PubMed=17006457; DOI=10.1038/ng1006-1091;
Rosand J., Bayley N., Rost N., de Bakker P.I.W.;
"Many hypotheses but no replication for the association between PDE4D
and stroke.";
Nat. Genet. 38:1091-1092(2006).
[16]
INTERACTION WITH SHANK2, AND TISSUE SPECIFICITY.
PubMed=17244609; DOI=10.1074/jbc.M610857200;
Lee J.H., Richter W., Namkung W., Kim K.H., Kim E., Conti M.,
Lee M.G.;
"Dynamic regulation of cystic fibrosis transmembrane conductance
regulator by competitive interactions of molecular adaptors.";
J. Biol. Chem. 282:10414-10422(2007).
[17]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Platelet;
PubMed=18088087; DOI=10.1021/pr0704130;
Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
Schuetz C., Walter U., Gambaryan S., Sickmann A.;
"Phosphoproteome of resting human platelets.";
J. Proteome Res. 7:526-534(2008).
[18]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-59 AND SER-63 (ISOFORMS
12; 5 AND N3), AND 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).
[19]
SUMOYLATION AT LYS-387 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).
[20]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=20068231; DOI=10.1126/scisignal.2000475;
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
Mann M.;
"Quantitative phosphoproteomics reveals widespread full
phosphorylation site occupancy during mitosis.";
Sci. Signal. 3:RA3-RA3(2010).
[21]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-299 AND SER-301, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21406692; DOI=10.1126/scisignal.2001570;
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
Blagoev B.;
"System-wide temporal characterization of the proteome and
phosphoproteome of human embryonic stem cell differentiation.";
Sci. Signal. 4:RS3-RS3(2011).
[22]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-348 AND SER-375, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
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).
[23]
X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 388-715 IN COMPLEX WITH THE
INHIBITOR ZARDAVERINE AND DIVALENT METAL IONS, AND MUTAGENESIS OF
ASP-527 AND ARG-563.
PubMed=12387865; DOI=10.1016/S0014-5793(02)03396-3;
Lee M.E., Markowitz J., Lee J.-O., Lee H.;
"Crystal structure of phosphodiesterase 4D and inhibitor complex.";
FEBS Lett. 530:53-58(2002).
[24]
X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 381-739 IN COMPLEX WITH CAMP
AND DIVALENT METAL IONS.
PubMed=14609333; DOI=10.1021/bi034653e;
Huai Q., Colicelli J., Ke H.;
"The crystal structure of AMP-bound PDE4 suggests a mechanism for
phosphodiesterase catalysis.";
Biochemistry 42:13220-13226(2003).
[25]
X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 381-739 IN COMPLEX WITH
INHIBITOR.
PubMed=12842049; DOI=10.1016/S0969-2126(03)00123-0;
Huai Q., Wang H., Sun Y., Kim H.Y., Liu Y., Ke H.;
"Three-dimensional structures of PDE4D in complex with roliprams and
implication on inhibitor selectivity.";
Structure 11:865-873(2003).
[26]
X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 381-714 IN COMPLEX WITH METAL
IONS AND INHIBITOR.
PubMed=14668322; DOI=10.1074/jbc.M311556200;
Huai Q., Liu Y., Francis S.H., Corbin J.D., Ke H.;
"Crystal structures of phosphodiesterases 4 and 5 in complex with
inhibitor 3-isobutyl-1-methylxanthine suggest a conformation
determinant of inhibitor selectivity.";
J. Biol. Chem. 279:13095-13101(2004).
[27]
X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 380-756 IN COMPLEX WITH AMP;
METAL IONS AND THE INHIBITOR ROLIPRAM.
PubMed=15003452; DOI=10.1016/j.jmb.2004.01.040;
Xu R.X., Rocque W.J., Lambert M.H., Vanderwall D.E., Luther M.A.,
Nolte R.T.;
"Crystal structures of the catalytic domain of phosphodiesterase 4B
complexed with AMP, 8-Br-AMP, and rolipram.";
J. Mol. Biol. 337:355-365(2004).
[28]
X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 388-715 IN COMPLEX WITH AMP;
METAL IONS AND THE INHIBITOR ROLIPRAM, FUNCTION, AND COFACTOR.
PubMed=15260978; DOI=10.1016/j.molcel.2004.07.005;
Zhang K.Y.J., Card G.L., Suzuki Y., Artis D.R., Fong D., Gillette S.,
Hsieh D., Neiman J., West B.L., Zhang C., Milburn M.V., Kim S.-H.,
Schlessinger J., Bollag G.;
"A glutamine switch mechanism for nucleotide selectivity by
phosphodiesterases.";
Mol. Cell 15:279-286(2004).
[29]
X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS) OF 388-715 IN COMPLEX WITH
METAL IONS AND INHIBITORS, FUNCTION, AND COFACTOR.
PubMed=15576036; DOI=10.1016/j.str.2004.10.004;
Card G.L., England B.P., Suzuki Y., Fong D., Powell B., Lee B.,
Luu C., Tabrizizad M., Gillette S., Ibrahim P.N., Artis D.R.,
Bollag G., Milburn M.V., Kim S.-H., Schlessinger J., Zhang K.Y.J.;
"Structural basis for the activity of drugs that inhibit
phosphodiesterases.";
Structure 12:2233-2247(2004).
[30]
X-RAY CRYSTALLOGRAPHY (1.36 ANGSTROMS) OF 388-715 IN COMPLEX WITH
METAL IONS AND INHIBITORS.
PubMed=15685167; DOI=10.1038/nbt1059;
Card G.L., Blasdel L., England B.P., Zhang C., Suzuki Y., Gillette S.,
Fong D., Ibrahim P.N., Artis D.R., Bollag G., Milburn M.V., Kim S.-H.,
Schlessinger J., Zhang K.Y.J.;
"A family of phosphodiesterase inhibitors discovered by
cocrystallography and scaffold-based drug design.";
Nat. Biotechnol. 23:201-207(2005).
[31]
X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 381-741 IN COMPLEX WITH
METAL IONS AND INHIBITORS.
PubMed=16539372; DOI=10.1021/jm051273d;
Huai Q., Sun Y., Wang H., Macdonald D., Aspiotis R., Robinson H.,
Huang Z., Ke H.;
"Enantiomer discrimination illustrated by the high resolution crystal
structures of type 4 phosphodiesterase.";
J. Med. Chem. 49:1867-1873(2006).
[32]
X-RAY CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 388-715 IN COMPLEX WITH
METAL IONS AND THE INHIBITOR NVP.
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).
[33]
STRUCTURE BY NMR OF N-TERMINUS OF ISOFORM 5/N3/12, AND INTERACTION
WITH RACK1.
PubMed=17900862; DOI=10.1016/j.cellsig.2007.08.015;
Smith K.J., Baillie G.S., Hyde E.I., Li X., Houslay T.M., McCahill A.,
Dunlop A.J., Bolger G.B., Klussmann E., Adams D.R., Houslay M.D.;
"1H NMR structural and functional characterisation of a cAMP-specific
phosphodiesterase-4D5 (PDE4D5) N-terminal region peptide that disrupts
PDE4D5 interaction with the signalling scaffold proteins, beta-
arrestin and RACK1.";
Cell. Signal. 19:2612-2624(2007).
[34]
X-RAY CRYSTALLOGRAPHY (1.56 ANGSTROMS) OF 388-714 OF MUTANT ASN-503 IN
COMPLEX WITH CAMP AND METAL IONS.
PubMed=17582435; DOI=10.1016/j.jmb.2007.05.060;
Wang H., Robinson H., Ke H.;
"The molecular basis for different recognition of substrates by
phosphodiesterase families 4 and 10.";
J. Mol. Biol. 371:302-307(2007).
[35]
VARIANTS ACRDYS2 ALA-190; THR-225; SER-226 AND PRO-587.
PubMed=22464250; DOI=10.1016/j.ajhg.2012.03.003;
Michot C., Le Goff C., Goldenberg A., Abhyankar A., Klein C.,
Kinning E., Guerrot A.M., Flahaut P., Duncombe A., Baujat G.,
Lyonnet S., Thalassinos C., Nitschke P., Casanova J.L., Le Merrer M.,
Munnich A., Cormier-Daire V.;
"Exome sequencing identifies PDE4D mutations as another cause of
acrodysostosis.";
Am. J. Hum. Genet. 90:740-745(2012).
[36]
VARIANTS ACRDYS2 GLU-228; ALA-590 AND ASP-673.
PubMed=22464252; DOI=10.1016/j.ajhg.2012.03.004;
Lee H., Graham J.M. Jr., Rimoin D.L., Lachman R.S., Krejci P.,
Tompson S.W., Nelson S.F., Krakow D., Cohn D.H.;
"Exome sequencing identifies PDE4D mutations in acrodysostosis.";
Am. J. Hum. Genet. 90:746-751(2012).
[37]
VARIANTS ACRDYS2 SER-227 AND ALA-590.
PubMed=23043190; DOI=10.1210/jc.2012-2326;
Linglart A., Fryssira H., Hiort O., Holterhus P.M.,
Perez de Nanclares G., Argente J., Heinrichs C., Kuechler A.,
Mantovani G., Leheup B., Wicart P., Chassot V., Schmidt D.,
Rubio-Cabezas O., Richter-Unruh A., Berrade S., Pereda A., Boros E.,
Munoz-Calvo M.T., Castori M., Gunes Y., Bertrand G., Bougneres P.,
Clauser E., Silve C.;
"PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct
syndromes with or without GPCR-signaling hormone resistance.";
J. Clin. Endocrinol. Metab. 97:E2328-E2338(2012).
[38]
VARIANTS ACRDYS2 THR-225; THR-301; VAL-304; ALA-329 AND THR-678.
PubMed=23033274; DOI=10.1002/humu.22222;
FORGE Canada Consortium;
Lynch D.C., Dyment D.A., Huang L., Nikkel S.M., Lacombe D.,
Campeau P.M., Lee B., Bacino C.A., Michaud J.L., Bernier F.P.,
Parboosingh J.S., Innes A.M.;
"Identification of novel mutations confirms Pde4d as a major gene
causing acrodysostosis.";
Hum. Mutat. 34:97-102(2013).
-!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key
regulator of many important physiological processes.
{ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036}.
-!- 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:15260978,
ECO:0000269|PubMed:15576036};
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:15260978,
ECO:0000269|PubMed:15576036};
-!- ENZYME REGULATION: Inhibited by rolipram. Activated by
phosphatidic acid. {ECO:0000269|PubMed:15131123}.
-!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from
3',5'-cyclic AMP: step 1/1.
-!- SUBUNIT: Homodimer for the long isoforms. Isoforms with truncated
N-termini are monomeric. Isoform 3 is part of a ternary complex
containing PRKAR2A, PRKAR2B and AKAP9. Interacts with PDE4DIP.
Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and
protein phosphatase 1 (PP1) (By similarity). Isoform 5, isoform N3
and isoform 12 bind RACK1 via their unique N-terminus. Binds
ARRB2. Interacts (via N-terminal region) with SHANK2 (via proline-
rich region); the interaction is increased in a PKA-dependent
manner. {ECO:0000250, ECO:0000269|PubMed:12193273,
ECO:0000269|PubMed:12387865, ECO:0000269|PubMed:12842049,
ECO:0000269|PubMed:14500724, ECO:0000269|PubMed:14609333,
ECO:0000269|PubMed:14668322, ECO:0000269|PubMed:15003452,
ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036,
ECO:0000269|PubMed:15685167, ECO:0000269|PubMed:16539372,
ECO:0000269|PubMed:17244609, ECO:0000269|PubMed:17582435,
ECO:0000269|PubMed:17727341, ECO:0000269|PubMed:17900862}.
-!- INTERACTION:
P26769:Adcy2 (xeno); NbExp=3; IntAct=EBI-8095525, EBI-1027877;
P32121:ARRB2; NbExp=2; IntAct=EBI-1642831, EBI-714559;
P38432:COIL; NbExp=3; IntAct=EBI-1642831, EBI-945751;
Q0D2H9:GOLGA8DP; NbExp=3; IntAct=EBI-1642831, EBI-10181276;
Q08AF8:GOLGA8G; NbExp=3; IntAct=EBI-1642831, EBI-10181260;
P43360:MAGEA6; NbExp=3; IntAct=EBI-1642831, EBI-1045155;
Q13077:TRAF1; NbExp=3; IntAct=EBI-1642831, EBI-359224;
Q8IUH5:ZDHHC17; NbExp=2; IntAct=EBI-9090666, EBI-524753;
-!- SUBCELLULAR LOCATION: Apical cell membrane
{ECO:0000269|PubMed:14500724}. Cytoplasm {ECO:0000250}. Membrane
{ECO:0000250}. Cytoplasm, cytoskeleton {ECO:0000250}. Cytoplasm,
cytoskeleton, microtubule organizing center, centrosome
{ECO:0000250}. Note=Found in the soluble fraction, associated with
membranes, and associated with the cytoskeleton and the centrosome
(By similarity). Colocalized with SHANK2 to the apical membrane of
colonic crypt cells. {ECO:0000250}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=12;
Name=4; Synonyms=hPDE4D4;
IsoId=Q08499-1; Sequence=Displayed;
Name=3; Synonyms=hPDE4D3;
IsoId=Q08499-2; Sequence=VSP_004577;
Note=Contains a phosphoserine at position 53. Activated by
phosphorylation at Ser-53. Mutagenesis of Ser-53 abolishes
activation. {ECO:0000269|PubMed:15131123};
Name=10;
IsoId=Q08499-3; Sequence=VSP_004578;
Name=1; Synonyms=hPDE4D1;
IsoId=Q08499-4; Sequence=VSP_004579;
Name=2; Synonyms=hPDE4D2;
IsoId=Q08499-5; Sequence=VSP_004580;
Name=5; Synonyms=hPDE4D5;
IsoId=Q08499-6; Sequence=VSP_012384;
Note=Contains a phosphoserine at position 59. Contains a
phosphoserine at position 63. {ECO:0000244|PubMed:18669648};
Name=N3; Synonyms=PDE4DN3;
IsoId=Q08499-7; Sequence=VSP_012384, VSP_012391, VSP_012392;
Note=Contains a phosphoserine at position 59. Contains a
phosphoserine at position 63. {ECO:0000244|PubMed:18669648};
Name=6; Synonyms=PDE4D6;
IsoId=Q08499-8; Sequence=VSP_012383, VSP_012393;
Name=8; Synonyms=PDE4D8;
IsoId=Q08499-9; Sequence=VSP_012386, VSP_012389;
Name=9; Synonyms=PDE4D9;
IsoId=Q08499-10; Sequence=VSP_012385, VSP_012390;
Name=7; Synonyms=PDE4D7;
IsoId=Q08499-11; Sequence=VSP_012387, VSP_012388;
Name=12;
IsoId=Q08499-12; Sequence=VSP_012384, VSP_023326, VSP_023327;
Note=Contains a phosphoserine at position 59. Contains a
phosphoserine at position 63. {ECO:0000244|PubMed:18669648};
-!- TISSUE SPECIFICITY: Expressed in colonic epithelial cells (at
protein level). Widespread; most abundant in skeletal muscle.
Isoform 6 is detected in brain. Isoform 8 is detected in brain,
placenta, lung and kidney. Isoform 7 is detected in heart and
skeletal muscle. {ECO:0000269|PubMed:12834813,
ECO:0000269|PubMed:17244609}.
-!- PTM: Long isoforms that share a conserved PKA phosphorylation site
in the N-terminus are activated by PKA through phosphorylation (By
similarity). Isoform 3 and isoform 7 are activated by
phosphorylation (in vitro), but not isoform 6. Isoform N3 and
isoform 12 are phosphorylated on Ser-49, Ser-51, Ser-55 and Ser-
59. {ECO:0000250}.
-!- PTM: Sumoylation of long isoforms by PIAS4 augments their
activation by PKA phosphorylation and represses their inhibition
by ERK phosphorylation. {ECO:0000269|PubMed:20196770}.
-!- DISEASE: Note=Genetic variations in PDE4D might be associated with
susceptibility to stroke. PubMed:17006457 states that association
with stroke has to be considered with caution.
{ECO:0000269|PubMed:17006457}.
-!- DISEASE: Acrodysostosis 2, with or without hormone resistance
(ACRDYS2) [MIM:614613]: A pleiotropic disorder characterized by
skeletal, endocrine, and neurological abnormalities. Skeletal
features include brachycephaly, midface hypoplasia with a small
upturned nose, brachydactyly, and lumbar spinal stenosis.
Endocrine abnormalities include hypothyroidism and hypogonadism in
males and irregular menses in females. Developmental disability is
a common finding but is variable in severity and can be associated
with significant behavioral problems.
{ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252,
ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}.
Note=The disease is caused by mutations affecting the gene
represented in this entry.
-!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase
family. PDE4 subfamily. {ECO:0000305}.
-!- WEB RESOURCE: Name=phosphodiesterase 4D, cAMP-specific
(phosphodiesterase E3 dunce homolog, Drosophila) (PDE4D);
Note=Leiden Open Variation Database (LOVD);
URL="http://www.lovd.nl/PDE4D";
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EMBL; L20970; AAA03592.1; -; mRNA.
EMBL; L20969; AAC00042.1; -; mRNA.
EMBL; U02882; AAC13745.1; -; mRNA.
EMBL; U50157; AAA97890.1; -; mRNA.
EMBL; U50158; AAA97891.1; -; mRNA.
EMBL; U50159; AAA97892.1; -; mRNA.
EMBL; AF012074; AAC00070.1; -; mRNA.
EMBL; AF012073; AAC00069.1; -; mRNA.
EMBL; AJ250854; CAC03757.1; -; mRNA.
EMBL; AF536975; AAN10117.1; -; mRNA.
EMBL; AF536976; AAN10118.1; -; mRNA.
EMBL; AF536977; AAN10119.1; -; mRNA.
EMBL; AY388960; AAQ90404.1; -; mRNA.
EMBL; AY245866; AAP75760.1; -; mRNA.
EMBL; AY245867; AAP75761.1; -; mRNA.
EMBL; BT007398; AAP36062.1; -; mRNA.
EMBL; BC008390; AAH08390.1; -; mRNA.
EMBL; BC036319; AAH36319.1; -; mRNA.
CCDS; CCDS47213.1; -. [Q08499-1]
CCDS; CCDS54858.1; -. [Q08499-2]
CCDS; CCDS54859.1; -. [Q08499-11]
CCDS; CCDS56369.1; -. [Q08499-8]
CCDS; CCDS56370.1; -. [Q08499-5]
CCDS; CCDS56371.1; -. [Q08499-10]
CCDS; CCDS56372.1; -. [Q08499-9]
CCDS; CCDS56373.1; -. [Q08499-6]
PIR; I61358; I61358.
RefSeq; NP_001098101.1; NM_001104631.1. [Q08499-1]
RefSeq; NP_001159371.1; NM_001165899.1. [Q08499-11]
RefSeq; NP_001184147.1; NM_001197218.1. [Q08499-6]
RefSeq; NP_001184148.1; NM_001197219.1. [Q08499-9]
RefSeq; NP_001184149.1; NM_001197220.1. [Q08499-10]
RefSeq; NP_001184150.1; NM_001197221.1. [Q08499-5]
RefSeq; NP_001184151.1; NM_001197222.1.
RefSeq; NP_001184152.1; NM_001197223.1. [Q08499-8]
RefSeq; NP_006194.2; NM_006203.4. [Q08499-2]
RefSeq; XP_005248595.1; XM_005248538.4. [Q08499-2]
RefSeq; XP_011541773.1; XM_011543471.1. [Q08499-11]
RefSeq; XP_011541775.1; XM_011543473.1. [Q08499-11]
RefSeq; XP_016865055.1; XM_017009566.1. [Q08499-11]
UniGene; Hs.117545; -.
PDB; 1E9K; NMR; -; A=-.
PDB; 1MKD; X-ray; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=388-715.
PDB; 1OYN; X-ray; 2.00 A; A/B/C/D=381-740.
PDB; 1PTW; X-ray; 2.30 A; A/B/C/D=381-740.
PDB; 1Q9M; X-ray; 2.30 A; A/B/C/D=381-740.
PDB; 1TB7; X-ray; 1.63 A; A/B=388-715.
PDB; 1TBB; X-ray; 1.60 A; A/B=388-715.
PDB; 1XOM; X-ray; 1.55 A; A/B=388-715.
PDB; 1XON; X-ray; 1.72 A; A/B=388-715.
PDB; 1XOQ; X-ray; 1.83 A; A/B=388-715.
PDB; 1XOR; X-ray; 1.54 A; A/B=388-715.
PDB; 1Y2B; X-ray; 1.40 A; A/B=388-715.
PDB; 1Y2C; X-ray; 1.67 A; A/B=388-715.
PDB; 1Y2D; X-ray; 1.70 A; A/B=388-715.
PDB; 1Y2E; X-ray; 2.10 A; A/B=388-715.
PDB; 1Y2K; X-ray; 1.36 A; A/B=388-715.
PDB; 1ZKN; X-ray; 2.10 A; A/B/C/D=381-714.
PDB; 2FM0; X-ray; 2.00 A; A/B/C/D=381-741.
PDB; 2FM5; X-ray; 2.03 A; A/B/C/D=381-741.
PDB; 2PW3; X-ray; 1.56 A; A/B=388-714.
PDB; 2QYN; X-ray; 1.57 A; A/B=388-715.
PDB; 3G4G; X-ray; 2.30 A; A/B/C/D=299-347, A/B/C/D=360-714.
PDB; 3G4I; X-ray; 1.90 A; A/B/C/D=380-753.
PDB; 3G4K; X-ray; 1.95 A; A/B/C/D=380-753.
PDB; 3G4L; X-ray; 2.50 A; A/B/C/D=380-753.
PDB; 3G58; X-ray; 2.05 A; A/B/C/D=380-753.
PDB; 3IAD; X-ray; 2.65 A; A/B/C/D=326-339, A/B/C/D=380-714.
PDB; 3IAK; X-ray; 2.80 A; A=388-715.
PDB; 3K4S; X-ray; 2.05 A; A=388-715.
PDB; 3SL3; X-ray; 2.10 A; A/B/C/D=381-741.
PDB; 3SL4; X-ray; 1.90 A; A/B/C/D=381-741.
PDB; 3SL5; X-ray; 2.65 A; A/B/C/D=381-714.
PDB; 3SL6; X-ray; 2.44 A; A/B/C/D=381-741.
PDB; 3SL8; X-ray; 2.60 A; A/B/C/D=381-741.
PDB; 3V9B; X-ray; 2.10 A; A/B/C/D=381-740.
PDB; 4OGB; X-ray; 2.03 A; A/B/C/D=381-741.
PDB; 4W1O; X-ray; 2.20 A; A/B/C/D=381-739.
PDB; 4WCU; X-ray; 2.35 A; A/B/C/D=381-739.
PDB; 5K1I; X-ray; 2.61 A; A/B/C/D/E/F/G/H=388-713.
PDB; 5K32; X-ray; 1.99 A; A/B=390-713.
PDB; 5TKB; X-ray; 2.16 A; A/B/C/D=380-753.
PDB; 5WQA; X-ray; 2.30 A; A/B=381-714.
PDBsum; 1E9K; -.
PDBsum; 1MKD; -.
PDBsum; 1OYN; -.
PDBsum; 1PTW; -.
PDBsum; 1Q9M; -.
PDBsum; 1TB7; -.
PDBsum; 1TBB; -.
PDBsum; 1XOM; -.
PDBsum; 1XON; -.
PDBsum; 1XOQ; -.
PDBsum; 1XOR; -.
PDBsum; 1Y2B; -.
PDBsum; 1Y2C; -.
PDBsum; 1Y2D; -.
PDBsum; 1Y2E; -.
PDBsum; 1Y2K; -.
PDBsum; 1ZKN; -.
PDBsum; 2FM0; -.
PDBsum; 2FM5; -.
PDBsum; 2PW3; -.
PDBsum; 2QYN; -.
PDBsum; 3G4G; -.
PDBsum; 3G4I; -.
PDBsum; 3G4K; -.
PDBsum; 3G4L; -.
PDBsum; 3G58; -.
PDBsum; 3IAD; -.
PDBsum; 3IAK; -.
PDBsum; 3K4S; -.
PDBsum; 3SL3; -.
PDBsum; 3SL4; -.
PDBsum; 3SL5; -.
PDBsum; 3SL6; -.
PDBsum; 3SL8; -.
PDBsum; 3V9B; -.
PDBsum; 4OGB; -.
PDBsum; 4W1O; -.
PDBsum; 4WCU; -.
PDBsum; 5K1I; -.
PDBsum; 5K32; -.
PDBsum; 5TKB; -.
PDBsum; 5WQA; -.
ProteinModelPortal; Q08499; -.
SMR; Q08499; -.
BioGrid; 111170; 49.
CORUM; Q08499; -.
DIP; DIP-41115N; -.
IntAct; Q08499; 25.
MINT; MINT-92262; -.
STRING; 9606.ENSP00000345502; -.
BindingDB; Q08499; -.
ChEMBL; CHEMBL288; -.
DrugBank; DB06842; (4R)-4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one.
DrugBank; DB04149; (R)-Rolipram.
DrugBank; DB03606; (S)-Rolipram.
DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine.
DrugBank; DB02918; 6-(4-Difluoromethoxy-3-Methoxy-Phenyl)-2h-Pyridazin-3-One.
DrugBank; DB00131; Adenosine monophosphate.
DrugBank; DB05676; Apremilast.
DrugBank; DB00201; Caffeine.
DrugBank; DB03849; Cilomilast.
DrugBank; DB05219; Crisaborole.
DrugBank; DB00651; Dyphylline.
DrugBank; DB05266; Ibudilast.
DrugBank; DB01088; Iloprost.
DrugBank; DB05298; OPC-6535.
DrugBank; DB01791; Piclamilast.
DrugBank; DB01656; Roflumilast.
DrugBank; DB01954; Rolipram.
GuidetoPHARMACOLOGY; 1303; -.
iPTMnet; Q08499; -.
PhosphoSitePlus; Q08499; -.
BioMuta; PDE4D; -.
DMDM; 12644392; -.
MaxQB; Q08499; -.
PaxDb; Q08499; -.
PeptideAtlas; Q08499; -.
PRIDE; Q08499; -.
DNASU; 5144; -.
Ensembl; ENST00000309641; ENSP00000308485; ENSG00000113448. [Q08499-7]
Ensembl; ENST00000317118; ENSP00000321739; ENSG00000113448. [Q08499-8]
Ensembl; ENST00000340635; ENSP00000345502; ENSG00000113448. [Q08499-1]
Ensembl; ENST00000358923; ENSP00000351800; ENSG00000113448. [Q08499-5]
Ensembl; ENST00000360047; ENSP00000353152; ENSG00000113448. [Q08499-2]
Ensembl; ENST00000405755; ENSP00000384806; ENSG00000113448. [Q08499-9]
Ensembl; ENST00000502484; ENSP00000423094; ENSG00000113448. [Q08499-11]
Ensembl; ENST00000502575; ENSP00000425917; ENSG00000113448. [Q08499-12]
Ensembl; ENST00000503258; ENSP00000425605; ENSG00000113448. [Q08499-10]
Ensembl; ENST00000507116; ENSP00000424852; ENSG00000113448. [Q08499-6]
GeneID; 5144; -.
KEGG; hsa:5144; -.
UCSC; uc003jrs.4; human. [Q08499-1]
CTD; 5144; -.
DisGeNET; 5144; -.
EuPathDB; HostDB:ENSG00000113448.16; -.
GeneCards; PDE4D; -.
HGNC; HGNC:8783; PDE4D.
HPA; HPA045895; -.
MalaCards; PDE4D; -.
MIM; 600129; gene.
MIM; 614613; phenotype.
neXtProt; NX_Q08499; -.
OpenTargets; ENSG00000113448; -.
Orphanet; 950; Acrodysostosis.
Orphanet; 280651; Acrodysostosis with multiple hormone resistance.
PharmGKB; PA33130; -.
eggNOG; KOG3689; Eukaryota.
eggNOG; ENOG410XRI7; LUCA.
GeneTree; ENSGT00760000118889; -.
HOVERGEN; HBG108239; -.
KO; K13293; -.
OMA; QHEVEMP; -.
OrthoDB; EOG091G06CD; -.
PhylomeDB; Q08499; -.
TreeFam; TF314638; -.
BRENDA; 3.1.4.53; 2681.
Reactome; R-HSA-180024; DARPP-32 events.
Reactome; R-HSA-418555; G alpha (s) signalling events.
SignaLink; Q08499; -.
SIGNOR; Q08499; -.
UniPathway; UPA00762; UER00747.
ChiTaRS; PDE4D; human.
EvolutionaryTrace; Q08499; -.
GeneWiki; PDE4D; -.
GenomeRNAi; 5144; -.
PRO; PR:Q08499; -.
Proteomes; UP000005640; Chromosome 5.
Bgee; ENSG00000113448; -.
ExpressionAtlas; Q08499; baseline and differential.
Genevisible; Q08499; HS.
GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
GO; GO:0034704; C:calcium channel complex; IDA:BHF-UCL.
GO; GO:0005813; C:centrosome; IEA:Ensembl.
GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
GO; GO:0016020; C:membrane; IDA:BHF-UCL.
GO; GO:0031965; C:nuclear membrane; IDA:HPA.
GO; GO:0005886; C:plasma membrane; IDA:HPA.
GO; GO:0005891; C:voltage-gated calcium channel complex; IEA:Ensembl.
GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IDA:BHF-UCL.
GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; NAS:UniProtKB.
GO; GO:0051117; F:ATPase binding; IPI:BHF-UCL.
GO; GO:0031698; F:beta-2 adrenergic receptor binding; ISS:BHF-UCL.
GO; GO:0030552; F:cAMP binding; IDA:BHF-UCL.
GO; GO:0008144; F:drug binding; IPI:UniProtKB.
GO; GO:0019899; F:enzyme binding; ISS:BHF-UCL.
GO; GO:0044325; F:ion channel binding; IPI:BHF-UCL.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL.
GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:BHF-UCL.
GO; GO:0071875; P:adrenergic receptor signaling pathway; ISS:BHF-UCL.
GO; GO:0086024; P:adrenergic receptor signaling pathway involved in positive regulation of heart rate; IC:BHF-UCL.
GO; GO:0007568; P:aging; IEA:Ensembl.
GO; GO:0006198; P:cAMP catabolic process; IDA:BHF-UCL.
GO; GO:0019933; P:cAMP-mediated signaling; NAS:BHF-UCL.
GO; GO:0071320; P:cellular response to cAMP; IDA:BHF-UCL.
GO; GO:0071872; P:cellular response to epinephrine stimulus; IDA:BHF-UCL.
GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
GO; GO:0061028; P:establishment of endothelial barrier; ISS:UniProtKB.
GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
GO; GO:0045822; P:negative regulation of heart contraction; ISS:BHF-UCL.
GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; ISS:BHF-UCL.
GO; GO:1901898; P:negative regulation of relaxation of cardiac muscle; ISS:BHF-UCL.
GO; GO:0030593; P:neutrophil chemotaxis; IEA:Ensembl.
GO; GO:0032729; P:positive regulation of interferon-gamma production; IMP:BHF-UCL.
GO; GO:0032743; P:positive regulation of interleukin-2 production; IMP:BHF-UCL.
GO; GO:0032754; P:positive regulation of interleukin-5 production; IMP:BHF-UCL.
GO; GO:0030814; P:regulation of cAMP metabolic process; IEA:Ensembl.
GO; GO:0086004; P:regulation of cardiac muscle cell contraction; ISS:BHF-UCL.
GO; GO:1901844; P:regulation of cell communication by electrical coupling involved in cardiac conduction; IC:BHF-UCL.
GO; GO:0002027; P:regulation of heart rate; ISS:BHF-UCL.
GO; GO:0010469; P:regulation of receptor activity; ISS:BHF-UCL.
GO; GO:0010880; P:regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; ISS:BHF-UCL.
GO; GO:0060314; P:regulation of ryanodine-sensitive calcium-release channel activity; ISS:BHF-UCL.
GO; GO:0006939; P:smooth muscle contraction; IEA:Ensembl.
GO; GO:0050852; P:T cell receptor signaling pathway; IMP:BHF-UCL.
CDD; cd00077; HDc; 1.
Gene3D; 1.10.1300.10; -; 1.
InterPro; IPR003607; HD/PDEase_dom.
InterPro; IPR023088; PDEase.
InterPro; IPR002073; PDEase_catalytic_dom.
InterPro; IPR036971; PDEase_catalytic_dom_sf.
InterPro; IPR023174; PDEase_CS.
Pfam; PF00233; PDEase_I; 1.
PRINTS; PR00387; PDIESTERASE1.
PROSITE; PS00126; PDEASE_I; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; cAMP; Cell membrane;
Complete proteome; Cytoplasm; Cytoskeleton; Disease mutation;
Hydrolase; Isopeptide bond; Membrane; Metal-binding; Phosphoprotein;
Reference proteome; Ubl conjugation.
CHAIN 1 809 cAMP-specific 3',5'-cyclic
phosphodiesterase 4D.
/FTId=PRO_0000198814.
NP_BIND 462 466 cAMP. {ECO:0000269|PubMed:14609333,
ECO:0000269|PubMed:17582435}.
COMPBIAS 42 88 Pro-rich.
ACT_SITE 462 462 Proton donor. {ECO:0000250}.
METAL 466 466 Divalent metal cation 1.
METAL 502 502 Divalent metal cation 1.
METAL 503 503 Divalent metal cation 1.
METAL 503 503 Divalent metal cation 2.
METAL 620 620 Divalent metal cation 1.
BINDING 503 503 cAMP. {ECO:0000269|PubMed:14609333,
ECO:0000269|PubMed:17582435}.
BINDING 620 620 cAMP. {ECO:0000269|PubMed:14609333,
ECO:0000269|PubMed:17582435}.
BINDING 671 671 cAMP. {ECO:0000269|PubMed:14609333,
ECO:0000269|PubMed:17582435}.
SITE 623 623 Binds AMP, but not cAMP.
MOD_RES 142 142 Phosphoserine.
{ECO:0000250|UniProtKB:P14270}.
MOD_RES 299 299 Phosphoserine.
{ECO:0000244|PubMed:21406692}.
MOD_RES 301 301 Phosphoserine.
{ECO:0000244|PubMed:21406692}.
MOD_RES 348 348 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 375 375 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
CROSSLNK 387 387 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO).
VAR_SEQ 1 302 Missing (in isoform 2).
{ECO:0000303|PubMed:8797812,
ECO:0000303|PubMed:9371713}.
/FTId=VSP_004580.
VAR_SEQ 1 291 Missing (in isoform 6).
{ECO:0000303|PubMed:12834813,
ECO:0000303|PubMed:15489334}.
/FTId=VSP_012383.
VAR_SEQ 1 269 MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQY
PLRQPQFRLLHPHHHLPPPPPPSPQPQPQCPLQPPPPPPLP
PPPPPPGAARGRYASSGATGRVRHRGYSDTERYLYCRAMDR
TSYAVETGHRPGLKKSRMSWPSSFQGLRRFDVDNGTSAGRS
PLDPMTSPGSGLILQANFVHSQRRESFLYRSDSDYDLSPKS
MSRNSSIASDIHGDDLIVTPFAQVLASLRTVRNNFAALTNL
QDRAPSKRSPMCNQPSINKATIT -> MKEQPSCAGTGHPM
AGYGRMAPFELASGPVKRLRTESPFPCLFA (in
isoform 1). {ECO:0000303|PubMed:8797812,
ECO:0000303|PubMed:9371713}.
/FTId=VSP_004579.
VAR_SEQ 1 205 Missing (in isoform 10).
{ECO:0000303|PubMed:8125310,
ECO:0000303|PubMed:9371713}.
/FTId=VSP_004578.
VAR_SEQ 1 152 MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQY
PLRQPQFRLLHPHHHLPPPPPPSPQPQPQCPLQPPPPPPLP
PPPPPPGAARGRYASSGATGRVRHRGYSDTERYLYCRAMDR
TSYAVETGHRPGLKKSRMSWPSSFQGLRR -> MMHVNNFP
FRRHSWIC (in isoform 3).
{ECO:0000303|PubMed:8413254,
ECO:0000303|PubMed:9371713}.
/FTId=VSP_004577.
VAR_SEQ 1 152 MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQY
PLRQPQFRLLHPHHHLPPPPPPSPQPQPQCPLQPPPPPPLP
PPPPPPGAARGRYASSGATGRVRHRGYSDTERYLYCRAMDR
TSYAVETGHRPGLKKSRMSWPSSFQGLRR -> MAQQTSPD
TLTVPEVDNPHCPNPWLNEDLVKSLRENLLQHEKSKTARKS
VSPKLSPVISPRNSPRLLRRMLLSSNIPKQRRFTVAHTC
(in isoform 5, isoform N3 and isoform
12). {ECO:0000303|PubMed:10913353,
ECO:0000303|PubMed:15489334,
ECO:0000303|PubMed:9371713,
ECO:0000303|Ref.9}.
/FTId=VSP_012384.
VAR_SEQ 1 130 Missing (in isoform 9).
{ECO:0000303|PubMed:12834813,
ECO:0000303|PubMed:14517540}.
/FTId=VSP_012385.
VAR_SEQ 1 122 Missing (in isoform 8).
{ECO:0000303|PubMed:12834813}.
/FTId=VSP_012386.
VAR_SEQ 1 61 Missing (in isoform 7).
{ECO:0000303|PubMed:12834813,
ECO:0000303|PubMed:14517540}.
/FTId=VSP_012387.
VAR_SEQ 62 152 PPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATG
RVRHRGYSDTERYLYCRAMDRTSYAVETGHRPGLKKSRMSW
PSSFQGLRR -> MKRNTCDLLSRSKSASEETLHSSNEEED
PFRGMEPYLVRRLSCRNIQLPPLAFRQLEQADLKSESENIQ
RPTSLPLKILPLIAITSAESSG (in isoform 7).
{ECO:0000303|PubMed:12834813,
ECO:0000303|PubMed:14517540}.
/FTId=VSP_012388.
VAR_SEQ 123 152 RTSYAVETGHRPGLKKSRMSWPSSFQGLRR -> MAFVWDP
LGATVPGPSTRAKSRLRFSKSYS (in isoform 8).
{ECO:0000303|PubMed:12834813}.
/FTId=VSP_012389.
VAR_SEQ 131 152 GHRPGLKKSRMSWPSSFQGLRR -> MSIIMKPRSRSTSSL
RTAEAVC (in isoform 9).
{ECO:0000303|PubMed:12834813,
ECO:0000303|PubMed:14517540}.
/FTId=VSP_012390.
VAR_SEQ 270 283 EEAYQKLASETLEE -> GSWMELNPYTLLDM (in
isoform 12).
{ECO:0000303|PubMed:15489334,
ECO:0000303|Ref.9}.
/FTId=VSP_023326.
VAR_SEQ 270 279 EEAYQKLASE -> GLYNGIIAFL (in isoform N3).
{ECO:0000303|PubMed:10913353}.
/FTId=VSP_012391.
VAR_SEQ 280 809 Missing (in isoform N3).
{ECO:0000303|PubMed:10913353}.
/FTId=VSP_012392.
VAR_SEQ 284 809 Missing (in isoform 12).
{ECO:0000303|PubMed:15489334,
ECO:0000303|Ref.9}.
/FTId=VSP_023327.
VAR_SEQ 292 306 ETLQTRHSVSEMASN -> MPEANYLLSVSWGYI (in
isoform 6). {ECO:0000303|PubMed:12834813,
ECO:0000303|PubMed:15489334}.
/FTId=VSP_012393.
VARIANT 190 190 S -> A (in ACRDYS2; dbSNP:rs397514466).
{ECO:0000269|PubMed:22464250}.
/FTId=VAR_068242.
VARIANT 225 225 P -> T (in ACRDYS2; dbSNP:rs397514464).
{ECO:0000269|PubMed:22464250,
ECO:0000269|PubMed:23033274}.
/FTId=VAR_068243.
VARIANT 226 226 F -> S (in ACRDYS2; dbSNP:rs397514465).
{ECO:0000269|PubMed:22464250}.
/FTId=VAR_068244.
VARIANT 227 227 A -> S (in ACRDYS2).
{ECO:0000269|PubMed:23043190}.
/FTId=VAR_069448.
VARIANT 228 228 Q -> E (in ACRDYS2; dbSNP:rs397514468).
{ECO:0000269|PubMed:22464252}.
/FTId=VAR_069449.
VARIANT 301 301 S -> T (in ACRDYS2).
{ECO:0000269|PubMed:23033274}.
/FTId=VAR_069450.
VARIANT 304 304 A -> V (in ACRDYS2; dbSNP:rs397515433).
{ECO:0000269|PubMed:23033274}.
/FTId=VAR_069451.
VARIANT 329 329 V -> A (in ACRDYS2).
{ECO:0000269|PubMed:23033274}.
/FTId=VAR_069452.
VARIANT 587 587 T -> P (in ACRDYS2; dbSNP:rs397514467).
{ECO:0000269|PubMed:22464250}.
/FTId=VAR_068245.
VARIANT 590 590 E -> A (in ACRDYS2).
{ECO:0000269|PubMed:22464252,
ECO:0000269|PubMed:23043190}.
/FTId=VAR_069453.
VARIANT 673 673 G -> D (in ACRDYS2; dbSNP:rs397514469).
{ECO:0000269|PubMed:22464252}.
/FTId=VAR_069454.
VARIANT 678 678 I -> T (in ACRDYS2; dbSNP:rs587777188).
{ECO:0000269|PubMed:23033274}.
/FTId=VAR_069455.
MUTAGEN 503 503 D->N: Abolishes catalytic activity.
MUTAGEN 527 527 D->R: Abolishes homodimerization.
{ECO:0000269|PubMed:12387865}.
MUTAGEN 563 563 R->D: Abolishes homodimerization.
{ECO:0000269|PubMed:12387865}.
CONFLICT 510 510 S -> F (in Ref. 10; AAH36319).
{ECO:0000305}.
CONFLICT 549 549 D -> G (in Ref. 6; AAN10119).
{ECO:0000305}.
CONFLICT 644 644 R -> P (in Ref. 2). {ECO:0000305}.
CONFLICT 769 769 C -> R (in Ref. 3; AAA97890/AAA97891/
AAA97892). {ECO:0000305}.
STRAND 256 259 {ECO:0000244|PDB:1E9K}.
HELIX 261 265 {ECO:0000244|PDB:1E9K}.
TURN 266 271 {ECO:0000244|PDB:1E9K}.
STRAND 272 274 {ECO:0000244|PDB:1E9K}.
HELIX 275 280 {ECO:0000244|PDB:1E9K}.
STRAND 383 386 {ECO:0000244|PDB:1OYN}.
HELIX 389 397 {ECO:0000244|PDB:1Y2K}.
HELIX 398 400 {ECO:0000244|PDB:1Y2K}.
HELIX 408 414 {ECO:0000244|PDB:1Y2K}.
HELIX 419 430 {ECO:0000244|PDB:1Y2K}.
HELIX 433 436 {ECO:0000244|PDB:1Y2K}.
HELIX 441 453 {ECO:0000244|PDB:1Y2K}.
STRAND 460 463 {ECO:0000244|PDB:1Y2K}.
HELIX 464 478 {ECO:0000244|PDB:1Y2K}.
HELIX 481 483 {ECO:0000244|PDB:1Y2K}.
TURN 484 486 {ECO:0000244|PDB:1Y2K}.
HELIX 489 501 {ECO:0000244|PDB:1Y2K}.
TURN 502 505 {ECO:0000244|PDB:1Y2K}.
HELIX 511 516 {ECO:0000244|PDB:1Y2K}.
HELIX 520 525 {ECO:0000244|PDB:1Y2K}.
HELIX 530 541 {ECO:0000244|PDB:1Y2K}.
HELIX 542 544 {ECO:0000244|PDB:1Y2K}.
TURN 545 547 {ECO:0000244|PDB:5K32}.
TURN 550 553 {ECO:0000244|PDB:1Y2K}.
HELIX 556 571 {ECO:0000244|PDB:1Y2K}.
HELIX 575 577 {ECO:0000244|PDB:1Y2K}.
HELIX 578 590 {ECO:0000244|PDB:1Y2K}.
STRAND 598 600 {ECO:0000244|PDB:2QYN}.
HELIX 605 620 {ECO:0000244|PDB:1Y2K}.
HELIX 623 625 {ECO:0000244|PDB:1Y2K}.
HELIX 628 652 {ECO:0000244|PDB:1Y2K}.
TURN 658 660 {ECO:0000244|PDB:3SL3}.
HELIX 662 664 {ECO:0000244|PDB:5K32}.
HELIX 667 677 {ECO:0000244|PDB:1Y2K}.
HELIX 679 689 {ECO:0000244|PDB:1Y2K}.
TURN 690 694 {ECO:0000244|PDB:1Y2K}.
HELIX 695 710 {ECO:0000244|PDB:1Y2K}.
HELIX 730 734 {ECO:0000244|PDB:3G58}.
TURN 735 738 {ECO:0000244|PDB:3G58}.
SEQUENCE 809 AA; 91115 MW; 7A4773DD3A044F57 CRC64;
MEAEGSSAPA RAGSGEGSDS AGGATLKAPK HLWRHEQHHQ YPLRQPQFRL LHPHHHLPPP
PPPSPQPQPQ CPLQPPPPPP LPPPPPPPGA ARGRYASSGA TGRVRHRGYS DTERYLYCRA
MDRTSYAVET GHRPGLKKSR MSWPSSFQGL RRFDVDNGTS AGRSPLDPMT SPGSGLILQA
NFVHSQRRES FLYRSDSDYD LSPKSMSRNS SIASDIHGDD LIVTPFAQVL ASLRTVRNNF
AALTNLQDRA PSKRSPMCNQ PSINKATITE EAYQKLASET LEELDWCLDQ LETLQTRHSV
SEMASNKFKR MLNRELTHLS EMSRSGNQVS EFISNTFLDK QHEVEIPSPT QKEKEKKKRP
MSQISGVKKL MHSSSLTNSS IPRFGVKTEQ EDVLAKELED VNKWGLHVFR IAELSGNRPL
TVIMHTIFQE RDLLKTFKIP VDTLITYLMT LEDHYHADVA YHNNIHAADV VQSTHVLLST
PALEAVFTDL EILAAIFASA IHDVDHPGVS NQFLINTNSE LALMYNDSSV LENHHLAVGF
KLLQEENCDI FQNLTKKQRQ SLRKMVIDIV LATDMSKHMN LLADLKTMVE TKKVTSSGVL
LLDNYSDRIQ VLQNMVHCAD LSNPTKPLQL YRQWTDRIME EFFRQGDRER ERGMEISPMC
DKHNASVEKS QVGFIDYIVH PLWETWADLV HPDAQDILDT LEDNREWYQS TIPQSPSPAP
DDPEEGRQGQ TEKFQFELTL EEDGESDTEK DSGSQVEEDT SCSDSKTLCT QDSESTEIPL
DEQVEEEAVG EEEESQPEAC VIDDRSPDT


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