ID PDE4D_HUMAN Reviewed; 809 AA.
AC Q08499; O43433; Q13549; Q13550; Q13551; Q7Z2L8; Q8IV84; Q8IVA9; Q8IVD2;
AC Q8IVD3; Q96HL4; Q9HCX7;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 2.
DT 27-MAR-2024, entry version 235.
DE RecName: Full=3',5'-cyclic-AMP phosphodiesterase 4D {ECO:0000305};
DE EC=3.1.4.53 {ECO:0000269|PubMed:9371713};
DE AltName: Full=DPDE3;
DE AltName: Full=PDE43;
DE AltName: Full=cAMP-specific phosphodiesterase 4D {ECO:0000305};
GN Name=PDE4D {ECO:0000312|HGNC:HGNC:8783}; Synonyms=DPDE3;
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] (ISOFORMS 3 AND 4).
RX PubMed=8413254; DOI=10.1128/mcb.13.10.6558-6571.1993;
RA Bolger G., Michaeli T., Martins T., St John T., Steiner B., Rodgers L.,
RA Riggs M., Wigler M., Ferguson K.;
RT "A family of human phosphodiesterases homologous to the dunce learning and
RT memory gene product of Drosophila melanogaster are potential targets for
RT antidepressant drugs.";
RL Mol. Cell. Biol. 13:6558-6571(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 4).
RX PubMed=8797812; DOI=10.1016/0014-5793(96)00300-6;
RA Nemoz G., Zhang R.B., Sette C., Conti M.;
RT "Identification of cyclic AMP-phosphodiesterase variants from the PDE4D
RT gene expressed in human peripheral mononuclear cells.";
RL FEBS Lett. 384:97-102(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 10).
RC TISSUE=Heart;
RX PubMed=8125310; DOI=10.1016/0378-1119(94)90818-4;
RA Baecker P.A., Obernolte R., Bach C., Yee C., Shelton E.R.;
RT "Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP
RT phosphodiesterase (PDE IVD).";
RL Gene 138:253-256(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4; 5 AND 10), SEQUENCE
RP REVISION (ISOFORM 1), FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=9371713; DOI=10.1042/bj3280539;
RA Bolger G.B., Erdogan S., Jones R.E., Loughney K., Scotland G., Hoffmann R.,
RA Wilkinson I., Farrell C., Houslay M.D.;
RT "Characterization of five different proteins produced by alternatively
RT spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene.";
RL Biochem. J. 328:539-548(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM N3), AND ALTERNATIVE SPLICING.
RC TISSUE=Umbilical vein endothelial cell;
RX PubMed=10913353; DOI=10.1006/bbrc.2000.3146;
RA Miro X., Casacuberta J.M., Gutierrez-Lopez M.D., Landazuri M.O.,
RA Puigdomenech P.;
RT "Phosphodiesterases 4D and 7A splice variants in the response of HUVEC
RT cells to TNF-alpha1.";
RL Biochem. Biophys. Res. Commun. 274:415-421(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 6; 7; 8 AND 9), PHOSPHORYLATION, AND
RP TISSUE SPECIFICITY.
RX PubMed=12834813; DOI=10.1016/s0898-6568(03)00042-1;
RA Wang D., Deng C., Bugaj-Gaweda B., Kwan M., Gunwaldsen C., Leonard C.,
RA Xin X., Hu Y., Unterbeck A., De Vivo M.;
RT "Cloning and characterization of novel PDE4D isoforms PDE4D6 and PDE4D7.";
RL Cell. Signal. 15:883-891(2003).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 7 AND 9), AND INVOLVEMENT IN
RP SUSCEPTIBILITY TO STROKE.
RX PubMed=14517540; DOI=10.1038/ng1245;
RA Gretarsdottir S., Thorleifsson G., Reynisdottir S.T., Manolescu A.,
RA Jonsdottir S., Jonsdottir T., Gudmundsdottir T., Bjarnadottir S.M.,
RA Einarsson O.B., Gudjonsdottir H.M., Hawkins M., Gudmundsson G.,
RA Gudmundsdottir H., Andrason H., Gudmundsdottir A.S., Sigurdardottir M.,
RA Chou T.T., Nahmias J., Goss S., Sveinbjoernsdottir S., Valdimarsson E.M.,
RA Jakobsson F., Agnarsson U., Gudnason V., Thorgeirsson G., Fingerle J.,
RA Gurney M., Gudbjartsson D., Frigge M.L., Kong A., Stefansson K.,
RA Gulcher J.R.;
RT "The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.";
RL Nat. Genet. 35:131-138(2003).
RN [8]
RP ERRATUM OF PUBMED:14517540.
RA Gretarsdottir S., Thorleifsson G., Reynisdottir S.T., Manolescu A.,
RA Jonsdottir S., Jonsdottir T., Gudmundsdottir T., Bjarnadottir S.M.,
RA Einarsson O.B., Gudjonsdottir H.M., Hawkins M., Gudmundsson G.,
RA Gudmundsdottir H., Andrason H., Gudmundsdottir A.S., Sigurdardottir M.,
RA Chou T.T., Nahmias J., Goss S., Sveinbjoernsdottir S., Valdimarsson E.M.,
RA Jakobsson F., Agnarsson U., Gudnason V., Thorgeirsson G., Fingerle J.,
RA Gurney M., Gudbjartsson D., Frigge M.L., Kong A., Stefansson K.,
RA Gulcher J.R.;
RL Nat. Genet. 37:555-555(2005).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 12).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 6 AND 12).
RC TISSUE=Brain, and Testis;
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 [11]
RP INTERACTION WITH RACK1.
RX PubMed=12193273; DOI=10.1186/1471-2091-3-24;
RA Bolger G.B., McCahill A., Yarwood S.J., Steele M.S., Warwicker J.,
RA Houslay M.D.;
RT "Delineation of RAID1, the RACK1 interaction domain located within the
RT unique N-terminal region of the cAMP-specific phosphodiesterase, PDE4D5.";
RL BMC Biochem. 3:24-24(2002).
RN [12]
RP INTERACTION WITH ARRB2, AND SUBCELLULAR LOCATION.
RX PubMed=14500724; DOI=10.1074/jbc.m303772200;
RA Bolger G.B., McCahill A., Huston E., Cheung Y.F., McSorley T.,
RA Baillie G.S., Houslay M.D.;
RT "The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase
RT isoform confers preferential interaction with beta-arrestins.";
RL J. Biol. Chem. 278:49230-49238(2003).
RN [13]
RP HOMODIMERIZATION OF LONG ISOFORMS, ACTIVITY REGULATION BY ROLIPRAM AND
RP PHOSPHATIDIC ACID, AND PHOSPHORYLATION AT SER-54 (ISOFORM 3).
RX PubMed=15131123; DOI=10.1074/jbc.m312687200;
RA Richter W., Conti M.;
RT "The oligomerization state determines regulatory properties and inhibitor
RT sensitivity of type 4 cAMP-specific phosphodiesterases.";
RL J. Biol. Chem. 279:30338-30348(2004).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [15]
RP DISCUSSION OF INVOLVEMENT IN STROKE.
RX PubMed=17006457; DOI=10.1038/ng1006-1091;
RA Rosand J., Bayley N., Rost N., de Bakker P.I.W.;
RT "Many hypotheses but no replication for the association between PDE4D and
RT stroke.";
RL Nat. Genet. 38:1091-1092(2006).
RN [16]
RP INTERACTION WITH SHANK2, AND TISSUE SPECIFICITY.
RX PubMed=17244609; DOI=10.1074/jbc.m610857200;
RA Lee J.H., Richter W., Namkung W., Kim K.H., Kim E., Conti M., Lee M.G.;
RT "Dynamic regulation of cystic fibrosis transmembrane conductance regulator
RT by competitive interactions of molecular adaptors.";
RL J. Biol. Chem. 282:10414-10422(2007).
RN [17]
RP TISSUE SPECIFICITY (ISOFORM 6).
RX PubMed=17519386; DOI=10.1124/jpet.107.122218;
RA Cheung Y.F., Kan Z., Garrett-Engele P., Gall I., Murdoch H., Baillie G.S.,
RA Camargo L.M., Johnson J.M., Houslay M.D., Castle J.C.;
RT "PDE4B5, a novel, super-short, brain-specific cAMP phosphodiesterase-4
RT variant whose isoform-specifying N-terminal region is identical to that of
RT cAMP phosphodiesterase-4D6 (PDE4D6).";
RL J. Pharmacol. Exp. Ther. 322:600-609(2007).
RN [18]
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 [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-59 AND SER-63 (ISOFORMS 12; 5
RP AND N3), AND IDENTIFICATION BY 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 [20]
RP SUMOYLATION AT LYS-387 BY PIAS4.
RX PubMed=20196770; DOI=10.1042/bj20091672;
RA Li X., Vadrevu S., Dunlop A., Day J., Advant N., Troeger J., Klussmann E.,
RA Jaffrey E., Hay R.T., Adams D.R., Houslay M.D., Baillie G.S.;
RT "Selective SUMO modification of cAMP-specific phosphodiesterase-4D5
RT (PDE4D5) regulates the functional consequences of phosphorylation by PKA
RT and ERK.";
RL Biochem. J. 428:55-65(2010).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-299 AND SER-301, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-348 AND SER-375, 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 [24]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 388-715 IN COMPLEX WITH THE
RP INHIBITOR ZARDAVERINE AND DIVALENT METAL IONS, AND MUTAGENESIS OF ASP-527
RP AND ARG-563.
RX PubMed=12387865; DOI=10.1016/s0014-5793(02)03396-3;
RA Lee M.E., Markowitz J., Lee J.-O., Lee H.;
RT "Crystal structure of phosphodiesterase 4D and inhibitor complex.";
RL FEBS Lett. 530:53-58(2002).
RN [25] {ECO:0007744|PDB:1PTW}
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 381-739 IN COMPLEX WITH AMP AND
RP ZINC, AND COFACTOR.
RX PubMed=14609333; DOI=10.1021/bi034653e;
RA Huai Q., Colicelli J., Ke H.;
RT "The crystal structure of AMP-bound PDE4 suggests a mechanism for
RT phosphodiesterase catalysis.";
RL Biochemistry 42:13220-13226(2003).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 381-739 IN COMPLEX WITH INHIBITOR.
RX PubMed=12842049; DOI=10.1016/s0969-2126(03)00123-0;
RA Huai Q., Wang H., Sun Y., Kim H.Y., Liu Y., Ke H.;
RT "Three-dimensional structures of PDE4D in complex with roliprams and
RT implication on inhibitor selectivity.";
RL Structure 11:865-873(2003).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 381-714 IN COMPLEX WITH METAL IONS
RP AND INHIBITOR.
RX PubMed=14668322; DOI=10.1074/jbc.m311556200;
RA Huai Q., Liu Y., Francis S.H., Corbin J.D., Ke H.;
RT "Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor
RT 3-isobutyl-1-methylxanthine suggest a conformation determinant of inhibitor
RT selectivity.";
RL J. Biol. Chem. 279:13095-13101(2004).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 380-756 IN COMPLEX WITH AMP; METAL
RP IONS AND THE INHIBITOR ROLIPRAM.
RX PubMed=15003452; DOI=10.1016/j.jmb.2004.01.040;
RA Xu R.X., Rocque W.J., Lambert M.H., Vanderwall D.E., Luther M.A.,
RA Nolte R.T.;
RT "Crystal structures of the catalytic domain of phosphodiesterase 4B
RT complexed with AMP, 8-Br-AMP, and rolipram.";
RL J. Mol. Biol. 337:355-365(2004).
RN [29] {ECO:0007744|PDB:1TB7, ECO:0007744|PDB:1TBB}
RP X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) OF 388-715 IN COMPLEX WITH AMP;
RP ZINC; MAGNESIUM AND THE INHIBITOR ROLIPRAM, FUNCTION, AND COFACTOR.
RX PubMed=15260978; DOI=10.1016/j.molcel.2004.07.005;
RA Zhang K.Y.J., Card G.L., Suzuki Y., Artis D.R., Fong D., Gillette S.,
RA Hsieh D., Neiman J., West B.L., Zhang C., Milburn M.V., Kim S.-H.,
RA Schlessinger J., Bollag G.;
RT "A glutamine switch mechanism for nucleotide selectivity by
RT phosphodiesterases.";
RL Mol. Cell 15:279-286(2004).
RN [30] {ECO:0007744|PDB:1XOM, ECO:0007744|PDB:1XON, ECO:0007744|PDB:1XOQ, ECO:0007744|PDB:1XOR}
RP X-RAY CRYSTALLOGRAPHY (1.54 ANGSTROMS) OF 388-715 IN COMPLEX WITH ZINC;
RP MAGNESIUM AND INHIBITORS, FUNCTION, AND COFACTOR.
RX PubMed=15576036; DOI=10.1016/j.str.2004.10.004;
RA Card G.L., England B.P., Suzuki Y., Fong D., Powell B., Lee B., Luu C.,
RA Tabrizizad M., Gillette S., Ibrahim P.N., Artis D.R., Bollag G.,
RA Milburn M.V., Kim S.-H., Schlessinger J., Zhang K.Y.J.;
RT "Structural basis for the activity of drugs that inhibit
RT phosphodiesterases.";
RL Structure 12:2233-2247(2004).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (1.36 ANGSTROMS) OF 388-715 IN COMPLEX WITH METAL
RP IONS AND INHIBITORS.
RX PubMed=15685167; DOI=10.1038/nbt1059;
RA Card G.L., Blasdel L., England B.P., Zhang C., Suzuki Y., Gillette S.,
RA Fong D., Ibrahim P.N., Artis D.R., Bollag G., Milburn M.V., Kim S.-H.,
RA Schlessinger J., Zhang K.Y.J.;
RT "A family of phosphodiesterase inhibitors discovered by cocrystallography
RT and scaffold-based drug design.";
RL Nat. Biotechnol. 23:201-207(2005).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 381-741 IN COMPLEX WITH METAL
RP IONS AND INHIBITORS.
RX PubMed=16539372; DOI=10.1021/jm051273d;
RA Huai Q., Sun Y., Wang H., Macdonald D., Aspiotis R., Robinson H., Huang Z.,
RA Ke H.;
RT "Enantiomer discrimination illustrated by the high resolution crystal
RT structures of type 4 phosphodiesterase.";
RL J. Med. Chem. 49:1867-1873(2006).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 388-715 IN COMPLEX WITH METAL
RP IONS AND THE INHIBITOR NVP.
RX PubMed=17727341; DOI=10.1042/bj20070970;
RA Wang H., Peng M.-S., Chen Y., Geng J., Robinson H., Houslay M.D., Cai J.,
RA Ke H.;
RT "Structures of the four subfamilies of phosphodiesterase-4 provide insight
RT into the selectivity of their inhibitors.";
RL Biochem. J. 408:193-201(2007).
RN [34]
RP STRUCTURE BY NMR OF N-TERMINUS OF ISOFORM 5/N3/12, AND INTERACTION WITH
RP RACK1.
RX PubMed=17900862; DOI=10.1016/j.cellsig.2007.08.015;
RA Smith K.J., Baillie G.S., Hyde E.I., Li X., Houslay T.M., McCahill A.,
RA Dunlop A.J., Bolger G.B., Klussmann E., Adams D.R., Houslay M.D.;
RT "1H NMR structural and functional characterisation of a cAMP-specific
RT phosphodiesterase-4D5 (PDE4D5) N-terminal region peptide that disrupts
RT PDE4D5 interaction with the signalling scaffold proteins, beta-arrestin and
RT RACK1.";
RL Cell. Signal. 19:2612-2624(2007).
RN [35] {ECO:0007744|PDB:2PW3}
RP X-RAY CRYSTALLOGRAPHY (1.56 ANGSTROMS) OF 388-714 OF MUTANT ASN-503 IN
RP COMPLEX WITH 3',5'-CAMP AND METAL IONS, MUTAGENESIS OF ASP-503, AND
RP COFACTOR.
RX PubMed=17582435; DOI=10.1016/j.jmb.2007.05.060;
RA Wang H., Robinson H., Ke H.;
RT "The molecular basis for different recognition of substrates by
RT phosphodiesterase families 4 and 10.";
RL J. Mol. Biol. 371:302-307(2007).
RN [36]
RP VARIANTS ACRDYS2 ALA-190; THR-225; SER-226 AND PRO-587.
RX PubMed=22464250; DOI=10.1016/j.ajhg.2012.03.003;
RA Michot C., Le Goff C., Goldenberg A., Abhyankar A., Klein C., Kinning E.,
RA Guerrot A.M., Flahaut P., Duncombe A., Baujat G., Lyonnet S.,
RA Thalassinos C., Nitschke P., Casanova J.L., Le Merrer M., Munnich A.,
RA Cormier-Daire V.;
RT "Exome sequencing identifies PDE4D mutations as another cause of
RT acrodysostosis.";
RL Am. J. Hum. Genet. 90:740-745(2012).
RN [37]
RP VARIANTS ACRDYS2 GLU-228; ALA-590 AND ASP-673.
RX PubMed=22464252; DOI=10.1016/j.ajhg.2012.03.004;
RA Lee H., Graham J.M. Jr., Rimoin D.L., Lachman R.S., Krejci P.,
RA Tompson S.W., Nelson S.F., Krakow D., Cohn D.H.;
RT "Exome sequencing identifies PDE4D mutations in acrodysostosis.";
RL Am. J. Hum. Genet. 90:746-751(2012).
RN [38]
RP VARIANTS ACRDYS2 SER-227 AND ALA-590.
RX PubMed=23043190; DOI=10.1210/jc.2012-2326;
RA Linglart A., Fryssira H., Hiort O., Holterhus P.M., Perez de Nanclares G.,
RA Argente J., Heinrichs C., Kuechler A., Mantovani G., Leheup B., Wicart P.,
RA Chassot V., Schmidt D., Rubio-Cabezas O., Richter-Unruh A., Berrade S.,
RA Pereda A., Boros E., Munoz-Calvo M.T., Castori M., Gunes Y., Bertrand G.,
RA Bougneres P., Clauser E., Silve C.;
RT "PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct
RT syndromes with or without GPCR-signaling hormone resistance.";
RL J. Clin. Endocrinol. Metab. 97:E2328-E2338(2012).
RN [39]
RP VARIANTS ACRDYS2 THR-225; THR-301; VAL-304; ALA-329 AND THR-678.
RX PubMed=23033274; DOI=10.1002/humu.22222;
RG FORGE Canada Consortium;
RA Lynch D.C., Dyment D.A., Huang L., Nikkel S.M., Lacombe D., Campeau P.M.,
RA Lee B., Bacino C.A., Michaud J.L., Bernier F.P., Parboosingh J.S.,
RA Innes A.M.;
RT "Identification of novel mutations confirms Pde4d as a major gene causing
RT acrodysostosis.";
RL Hum. Mutat. 34:97-102(2013).
CC -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key
CC regulator of many important physiological processes.
CC {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036,
CC ECO:0000269|PubMed:9371713}.
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; EC=3.1.4.53;
CC Evidence={ECO:0000269|PubMed:9371713};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25278;
CC Evidence={ECO:0000305|PubMed:9371713};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:14609333, ECO:0000269|PubMed:15260978,
CC ECO:0000269|PubMed:15576036, ECO:0000269|PubMed:17582435};
CC Note=Binds 2 divalent metal cations per subunit. Site 1 may
CC preferentially bind zinc ions. {ECO:0000269|PubMed:14609333,
CC ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036,
CC ECO:0000269|PubMed:17582435};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:Q07343};
CC Note=Binds 2 divalent metal cations per subunit (PubMed:15260978,
CC PubMed:15576036). Site 2 has a preference for magnesium and/or
CC manganese ions (By similarity). {ECO:0000250|UniProtKB:Q07343,
CC ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036};
CC -!- ACTIVITY REGULATION: Inhibited by rolipram. Activated by phosphatidic
CC acid. {ECO:0000269|PubMed:15131123}.
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from
CC 3',5'-cyclic AMP: step 1/1. {ECO:0000269|PubMed:9371713}.
CC -!- SUBUNIT: Homodimer for the long isoforms. Isoforms with truncated N-
CC termini are monomeric. Isoform 3 is part of a ternary complex
CC containing PRKAR2A, PRKAR2B and AKAP9. Interacts with PDE4DIP.
CC Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and
CC protein phosphatase 1 (PP1) (By similarity). Isoform 5, isoform N3 and
CC isoform 12 bind RACK1 via their unique N-terminus. Binds ARRB2.
CC Interacts (via N-terminal region) with SHANK2 (via proline-rich
CC region); the interaction is increased in a PKA-dependent manner.
CC {ECO:0000250, ECO:0000269|PubMed:12193273, ECO:0000269|PubMed:12387865,
CC ECO:0000269|PubMed:12842049, ECO:0000269|PubMed:14500724,
CC ECO:0000269|PubMed:14609333, ECO:0000269|PubMed:14668322,
CC ECO:0000269|PubMed:15003452, ECO:0000269|PubMed:15260978,
CC ECO:0000269|PubMed:15576036, ECO:0000269|PubMed:15685167,
CC ECO:0000269|PubMed:16539372, ECO:0000269|PubMed:17244609,
CC ECO:0000269|PubMed:17582435, ECO:0000269|PubMed:17727341,
CC ECO:0000269|PubMed:17900862}.
CC -!- INTERACTION:
CC Q08499; P32121: ARRB2; NbExp=2; IntAct=EBI-1642831, EBI-714559;
CC Q08499; P38432: COIL; NbExp=3; IntAct=EBI-1642831, EBI-945751;
CC Q08499; Q0D2H9: GOLGA8DP; NbExp=3; IntAct=EBI-1642831, EBI-10181276;
CC Q08499; Q08AF8: GOLGA8G; NbExp=3; IntAct=EBI-1642831, EBI-10181260;
CC Q08499; P43360: MAGEA6; NbExp=3; IntAct=EBI-1642831, EBI-1045155;
CC Q08499; Q13077: TRAF1; NbExp=3; IntAct=EBI-1642831, EBI-359224;
CC Q08499-2; P32121: ARRB2; NbExp=2; IntAct=EBI-8095525, EBI-714559;
CC Q08499-2; P26769: Adcy2; Xeno; NbExp=3; IntAct=EBI-8095525, EBI-1027877;
CC Q08499-8; P38432: COIL; NbExp=3; IntAct=EBI-9090666, EBI-945751;
CC Q08499-8; Q96CV9: OPTN; NbExp=3; IntAct=EBI-9090666, EBI-748974;
CC Q08499-8; Q8IUH5: ZDHHC17; NbExp=2; IntAct=EBI-9090666, EBI-524753;
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:14500724}. Cytoplasm {ECO:0000250}. Membrane
CC {ECO:0000250}. Cytoplasm, cytoskeleton {ECO:0000250}. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome {ECO:0000250}.
CC Note=Found in the soluble fraction, associated with membranes, and
CC associated with the cytoskeleton and the centrosome (By similarity).
CC Colocalized with SHANK2 to the apical membrane of colonic crypt cells.
CC {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=12;
CC Name=4; Synonyms=hPDE4D4;
CC IsoId=Q08499-1; Sequence=Displayed;
CC Name=3; Synonyms=hPDE4D3;
CC IsoId=Q08499-2; Sequence=VSP_004577;
CC Name=10;
CC IsoId=Q08499-3; Sequence=VSP_004578;
CC Name=1; Synonyms=hPDE4D1;
CC IsoId=Q08499-4; Sequence=VSP_004579;
CC Name=2; Synonyms=hPDE4D2;
CC IsoId=Q08499-5; Sequence=VSP_004580;
CC Name=5; Synonyms=hPDE4D5;
CC IsoId=Q08499-6; Sequence=VSP_012384;
CC Name=N3; Synonyms=PDE4DN3;
CC IsoId=Q08499-7; Sequence=VSP_012384, VSP_012391, VSP_012392;
CC Name=6; Synonyms=PDE4D6 {ECO:0000303|PubMed:17519386};
CC IsoId=Q08499-8; Sequence=VSP_012383, VSP_012393;
CC Name=8; Synonyms=PDE4D8;
CC IsoId=Q08499-9; Sequence=VSP_012386, VSP_012389;
CC Name=9; Synonyms=PDE4D9;
CC IsoId=Q08499-10; Sequence=VSP_012385, VSP_012390;
CC Name=7; Synonyms=PDE4D7;
CC IsoId=Q08499-11; Sequence=VSP_012387, VSP_012388;
CC Name=12;
CC IsoId=Q08499-12; Sequence=VSP_012384, VSP_023326, VSP_023327;
CC -!- TISSUE SPECIFICITY: Expressed in colonic epithelial cells (at protein
CC level). Widespread; most abundant in skeletal muscle.
CC {ECO:0000269|PubMed:12834813, ECO:0000269|PubMed:17244609}.
CC -!- TISSUE SPECIFICITY: [Isoform 6]: Detected in brain.
CC {ECO:0000269|PubMed:12834813, ECO:0000269|PubMed:17519386}.
CC -!- TISSUE SPECIFICITY: [Isoform 8]: Detected in brain, placenta, lung and
CC kidney. {ECO:0000269|PubMed:12834813}.
CC -!- TISSUE SPECIFICITY: [Isoform 7]: Detected in heart and skeletal muscle.
CC {ECO:0000269|PubMed:12834813}.
CC -!- PTM: Long isoforms that share a conserved PKA phosphorylation site in
CC the N-terminus are activated by PKA through phosphorylation (By
CC similarity). Isoform 3 and isoform 7 are activated by phosphorylation
CC (in vitro), but not isoform 6. Isoform N3 and isoform 12 are
CC phosphorylated on Ser-49, Ser-51, Ser-55 and Ser-59. {ECO:0000250}.
CC -!- PTM: Sumoylation of long isoforms by PIAS4 augments their activation by
CC PKA phosphorylation and represses their inhibition by ERK
CC phosphorylation. {ECO:0000269|PubMed:20196770}.
CC -!- DISEASE: Note=Genetic variations in PDE4D might be associated with
CC susceptibility to stroke. PubMed:17006457 states that association with
CC stroke has to be considered with caution.
CC {ECO:0000269|PubMed:17006457}.
CC -!- DISEASE: Acrodysostosis 2, with or without hormone resistance (ACRDYS2)
CC [MIM:614613]: A pleiotropic disorder characterized by skeletal,
CC endocrine, and neurological abnormalities. Skeletal features include
CC brachycephaly, midface hypoplasia with a small upturned nose,
CC brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities
CC include hypothyroidism and hypogonadism in males and irregular menses
CC in females. Developmental disability is a common finding but is
CC variable in severity and can be associated with significant behavioral
CC problems. {ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252,
CC ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: [Isoform 3]: Activated by phosphorylation at Ser-53.
CC Mutagenesis of Ser-54 abolishes activation. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE4 subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=phosphodiesterase 4D, cAMP-specific
CC (phosphodiesterase E3 dunce homolog, Drosophila) (PDE4D); Note=Leiden
CC Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/PDE4D";
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DR EMBL; L20970; AAA03592.1; -; mRNA.
DR EMBL; L20969; AAC00042.1; -; mRNA.
DR EMBL; U02882; AAC13745.1; -; mRNA.
DR EMBL; U50157; AAA97890.1; -; mRNA.
DR EMBL; U50158; AAA97891.1; -; mRNA.
DR EMBL; U50159; AAA97892.1; -; mRNA.
DR EMBL; AF012074; AAC00070.1; -; mRNA.
DR EMBL; AF012073; AAC00069.1; -; mRNA.
DR EMBL; AJ250854; CAC03757.1; -; mRNA.
DR EMBL; AF536975; AAN10117.1; -; mRNA.
DR EMBL; AF536976; AAN10118.1; -; mRNA.
DR EMBL; AF536977; AAN10119.1; -; mRNA.
DR EMBL; AY388960; AAQ90404.1; -; mRNA.
DR EMBL; AY245866; AAP75760.1; -; mRNA.
DR EMBL; AY245867; AAP75761.1; -; mRNA.
DR EMBL; BT007398; AAP36062.1; -; mRNA.
DR EMBL; BC008390; AAH08390.1; -; mRNA.
DR EMBL; BC036319; AAH36319.1; -; mRNA.
DR CCDS; CCDS47213.1; -. [Q08499-1]
DR CCDS; CCDS54858.1; -. [Q08499-2]
DR CCDS; CCDS54859.1; -. [Q08499-11]
DR CCDS; CCDS56369.1; -. [Q08499-8]
DR CCDS; CCDS56370.1; -. [Q08499-5]
DR CCDS; CCDS56371.1; -. [Q08499-10]
DR CCDS; CCDS56372.1; -. [Q08499-9]
DR CCDS; CCDS56373.1; -. [Q08499-6]
DR CCDS; CCDS93714.1; -. [Q08499-12]
DR PIR; I61358; I61358.
DR RefSeq; NP_001098101.1; NM_001104631.1. [Q08499-1]
DR RefSeq; NP_001159371.1; NM_001165899.1. [Q08499-11]
DR RefSeq; NP_001184147.1; NM_001197218.1. [Q08499-6]
DR RefSeq; NP_001184148.1; NM_001197219.1. [Q08499-9]
DR RefSeq; NP_001184149.1; NM_001197220.1. [Q08499-10]
DR RefSeq; NP_001184150.1; NM_001197221.1. [Q08499-5]
DR RefSeq; NP_001184151.1; NM_001197222.1.
DR RefSeq; NP_001184152.1; NM_001197223.1. [Q08499-8]
DR RefSeq; NP_006194.2; NM_006203.4. [Q08499-2]
DR RefSeq; XP_005248595.1; XM_005248538.4.
DR RefSeq; XP_011541773.1; XM_011543471.1.
DR RefSeq; XP_011541775.1; XM_011543473.1. [Q08499-11]
DR RefSeq; XP_016865055.1; XM_017009566.1. [Q08499-11]
DR PDB; 1E9K; NMR; -; A=-.
DR PDB; 1MKD; X-ray; 2.90 A; A/B/C/D/E/F/G/H/I/J/K/L=388-715.
DR PDB; 1OYN; X-ray; 2.00 A; A/B/C/D=381-740.
DR PDB; 1PTW; X-ray; 2.30 A; A/B/C/D=381-740.
DR PDB; 1Q9M; X-ray; 2.30 A; A/B/C/D=381-740.
DR PDB; 1TB7; X-ray; 1.63 A; A/B=388-715.
DR PDB; 1TBB; X-ray; 1.60 A; A/B=388-715.
DR PDB; 1XOM; X-ray; 1.55 A; A/B=388-715.
DR PDB; 1XON; X-ray; 1.72 A; A/B=388-715.
DR PDB; 1XOQ; X-ray; 1.83 A; A/B=388-715.
DR PDB; 1XOR; X-ray; 1.54 A; A/B=388-715.
DR PDB; 1Y2B; X-ray; 1.40 A; A/B=388-715.
DR PDB; 1Y2C; X-ray; 1.67 A; A/B=388-715.
DR PDB; 1Y2D; X-ray; 1.70 A; A/B=388-715.
DR PDB; 1Y2E; X-ray; 2.10 A; A/B=388-715.
DR PDB; 1Y2K; X-ray; 1.36 A; A/B=388-715.
DR PDB; 1ZKN; X-ray; 2.10 A; A/B/C/D=381-714.
DR PDB; 2FM0; X-ray; 2.00 A; A/B/C/D=381-741.
DR PDB; 2FM5; X-ray; 2.03 A; A/B/C/D=381-741.
DR PDB; 2PW3; X-ray; 1.56 A; A/B=388-714.
DR PDB; 2QYN; X-ray; 1.57 A; A/B=388-715.
DR PDB; 3G4G; X-ray; 2.30 A; A/B/C/D=299-347, A/B/C/D=360-714.
DR PDB; 3G4I; X-ray; 1.90 A; A/B/C/D=380-753.
DR PDB; 3G4K; X-ray; 1.95 A; A/B/C/D=380-753.
DR PDB; 3G4L; X-ray; 2.50 A; A/B/C/D=380-753.
DR PDB; 3G58; X-ray; 2.05 A; A/B/C/D=380-753.
DR PDB; 3IAD; X-ray; 2.65 A; A/B/C/D=326-339, A/B/C/D=380-714.
DR PDB; 3IAK; X-ray; 2.80 A; A=388-715.
DR PDB; 3K4S; X-ray; 2.05 A; A=388-715.
DR PDB; 3SL3; X-ray; 2.10 A; A/B/C/D=381-741.
DR PDB; 3SL4; X-ray; 1.90 A; A/B/C/D=381-741.
DR PDB; 3SL5; X-ray; 2.65 A; A/B/C/D=381-714.
DR PDB; 3SL6; X-ray; 2.44 A; A/B/C/D=381-741.
DR PDB; 3SL8; X-ray; 2.60 A; A/B/C/D=381-741.
DR PDB; 3V9B; X-ray; 2.10 A; A/B/C/D=381-740.
DR PDB; 4OGB; X-ray; 2.03 A; A/B/C/D=381-741.
DR PDB; 4W1O; X-ray; 2.20 A; A/B/C/D=381-739.
DR PDB; 4WCU; X-ray; 2.35 A; A/B/C/D=381-739.
DR PDB; 5K1I; X-ray; 2.61 A; A/B/C/D/E/F/G/H=388-713.
DR PDB; 5K32; X-ray; 1.99 A; A/B=390-713.
DR PDB; 5LBO; X-ray; 2.25 A; A/B/C/D=381-740.
DR PDB; 5TKB; X-ray; 2.16 A; A/B/C/D=380-753.
DR PDB; 5WH5; X-ray; 1.80 A; A/B=388-714.
DR PDB; 5WH6; X-ray; 1.60 A; A/B=303-809.
DR PDB; 5WQA; X-ray; 2.30 A; A/B=381-714.
DR PDB; 6AKR; X-ray; 2.33 A; A/B/C/D=381-740.
DR PDB; 6BOJ; X-ray; 1.70 A; A/B/C/D=380-718, A/B/C/D=730-734.
DR PDB; 6F6U; X-ray; 1.83 A; A/B=380-714.
DR PDB; 6F8R; X-ray; 1.83 A; A/B=380-714.
DR PDB; 6F8T; X-ray; 1.80 A; A/B=380-714.
DR PDB; 6F8U; X-ray; 2.10 A; A/B=380-714.
DR PDB; 6F8V; X-ray; 1.85 A; A/B=380-714.
DR PDB; 6F8W; X-ray; 1.60 A; A/B=380-714.
DR PDB; 6F8X; X-ray; 1.95 A; A/B=380-715.
DR PDB; 6FDC; X-ray; 1.45 A; A/B=380-714.
DR PDB; 6FDI; X-ray; 1.90 A; A/B/C/D=381-740.
DR PDB; 6FE7; X-ray; 2.00 A; A/B/C/D=381-740.
DR PDB; 6FEB; X-ray; 1.93 A; A/B=381-740.
DR PDB; 6FET; X-ray; 1.88 A; A/B/C/D=381-740.
DR PDB; 6FT0; X-ray; 2.10 A; A/B/C/D=381-740.
DR PDB; 6FTA; X-ray; 2.34 A; A/B/C/D=381-740.
DR PDB; 6FTW; X-ray; 2.16 A; A/B/C/D=381-740.
DR PDB; 6FW3; X-ray; 1.78 A; A/B/C/D=381-740.
DR PDB; 6HWO; X-ray; 1.99 A; A/B/C/D=381-740.
DR PDB; 6IAG; X-ray; 2.00 A; A/B/C/D=381-740.
DR PDB; 6IBF; X-ray; 2.31 A; A/B/C/D=381-740.
DR PDB; 6IM6; X-ray; 1.70 A; A/B=388-715.
DR PDB; 6IMB; X-ray; 1.55 A; A/B=388-715.
DR PDB; 6IMD; X-ray; 1.50 A; A/B=388-715.
DR PDB; 6IMI; X-ray; 1.46 A; A/B=388-715.
DR PDB; 6IMO; X-ray; 1.55 A; A/B=388-715.
DR PDB; 6IMR; X-ray; 1.50 A; A/B=388-715.
DR PDB; 6IMT; X-ray; 1.48 A; A/B=388-715.
DR PDB; 6IND; X-ray; 1.87 A; A/B=388-715.
DR PDB; 6INK; X-ray; 1.70 A; A/B=388-715.
DR PDB; 6INM; X-ray; 2.00 A; A/B=388-715.
DR PDB; 6KJZ; X-ray; 2.20 A; A/B=387-714.
DR PDB; 6KK0; X-ray; 2.20 A; A/B=388-713.
DR PDB; 6LRM; X-ray; 1.45 A; A/B=388-715.
DR PDB; 6NJH; X-ray; 2.15 A; A/B/C/D=326-339, A/B/C/D=380-718.
DR PDB; 6NJI; X-ray; 2.45 A; A/B=326-339, A/B=380-718.
DR PDB; 6NJJ; X-ray; 2.30 A; A/B/C/D=326-339, A/B/C/D=380-718.
DR PDB; 6RCW; X-ray; 2.08 A; A/B/C/D=381-740.
DR PDB; 6ZBA; X-ray; 1.60 A; AAA/BBB/CCC/DDD=381-738.
DR PDB; 7A8Q; X-ray; 2.24 A; A/B/C/D=381-740.
DR PDB; 7A9V; X-ray; 2.17 A; A/B/C/D=381-740.
DR PDB; 7AAG; X-ray; 1.79 A; A/B/C/D=381-740.
DR PDB; 7AB9; X-ray; 2.19 A; A/B/C/D=381-740.
DR PDB; 7ABD; X-ray; 2.41 A; A/B/C/D=381-740.
DR PDB; 7ABE; X-ray; 1.83 A; A/B/C/D=381-740.
DR PDB; 7ABJ; X-ray; 2.11 A; A/B/C/D=381-740.
DR PDB; 7AY6; X-ray; 1.66 A; A/B=380-714.
DR PDB; 7B9H; X-ray; 1.50 A; A/B=380-714.
DR PDB; 7CBJ; X-ray; 1.50 A; A/B=388-715.
DR PDB; 7CBQ; X-ray; 1.59 A; A/B=388-715.
DR PDB; 7F2K; X-ray; 2.10 A; A/B=303-809.
DR PDB; 7F2L; X-ray; 2.10 A; A/B=303-809.
DR PDB; 7F2M; X-ray; 2.20 A; A/B=303-809.
DR PDB; 7W4X; X-ray; 2.20 A; A/B=380-751.
DR PDB; 7W4Y; X-ray; 2.10 A; A/B=380-751.
DR PDB; 7XAA; X-ray; 2.10 A; A/B=303-809.
DR PDB; 7XAB; X-ray; 2.00 A; A/B=303-809.
DR PDB; 7XBB; X-ray; 2.10 A; A/B=303-809.
DR PDB; 7YQF; X-ray; 1.54 A; A/B=388-715.
DR PDB; 7YSX; X-ray; 1.65 A; A/B=388-715.
DR PDB; 8K4C; X-ray; 2.10 A; A/B=388-715.
DR PDB; 8K4H; X-ray; 1.95 A; A/B=388-715.
DR PDB; 8W4Q; X-ray; 1.55 A; A/B=388-715.
DR PDB; 8W4R; X-ray; 1.37 A; A/B=388-715.
DR PDBsum; 1E9K; -.
DR PDBsum; 1MKD; -.
DR PDBsum; 1OYN; -.
DR PDBsum; 1PTW; -.
DR PDBsum; 1Q9M; -.
DR PDBsum; 1TB7; -.
DR PDBsum; 1TBB; -.
DR PDBsum; 1XOM; -.
DR PDBsum; 1XON; -.
DR PDBsum; 1XOQ; -.
DR PDBsum; 1XOR; -.
DR PDBsum; 1Y2B; -.
DR PDBsum; 1Y2C; -.
DR PDBsum; 1Y2D; -.
DR PDBsum; 1Y2E; -.
DR PDBsum; 1Y2K; -.
DR PDBsum; 1ZKN; -.
DR PDBsum; 2FM0; -.
DR PDBsum; 2FM5; -.
DR PDBsum; 2PW3; -.
DR PDBsum; 2QYN; -.
DR PDBsum; 3G4G; -.
DR PDBsum; 3G4I; -.
DR PDBsum; 3G4K; -.
DR PDBsum; 3G4L; -.
DR PDBsum; 3G58; -.
DR PDBsum; 3IAD; -.
DR PDBsum; 3IAK; -.
DR PDBsum; 3K4S; -.
DR PDBsum; 3SL3; -.
DR PDBsum; 3SL4; -.
DR PDBsum; 3SL5; -.
DR PDBsum; 3SL6; -.
DR PDBsum; 3SL8; -.
DR PDBsum; 3V9B; -.
DR PDBsum; 4OGB; -.
DR PDBsum; 4W1O; -.
DR PDBsum; 4WCU; -.
DR PDBsum; 5K1I; -.
DR PDBsum; 5K32; -.
DR PDBsum; 5LBO; -.
DR PDBsum; 5TKB; -.
DR PDBsum; 5WH5; -.
DR PDBsum; 5WH6; -.
DR PDBsum; 5WQA; -.
DR PDBsum; 6AKR; -.
DR PDBsum; 6BOJ; -.
DR PDBsum; 6F6U; -.
DR PDBsum; 6F8R; -.
DR PDBsum; 6F8T; -.
DR PDBsum; 6F8U; -.
DR PDBsum; 6F8V; -.
DR PDBsum; 6F8W; -.
DR PDBsum; 6F8X; -.
DR PDBsum; 6FDC; -.
DR PDBsum; 6FDI; -.
DR PDBsum; 6FE7; -.
DR PDBsum; 6FEB; -.
DR PDBsum; 6FET; -.
DR PDBsum; 6FT0; -.
DR PDBsum; 6FTA; -.
DR PDBsum; 6FTW; -.
DR PDBsum; 6FW3; -.
DR PDBsum; 6HWO; -.
DR PDBsum; 6IAG; -.
DR PDBsum; 6IBF; -.
DR PDBsum; 6IM6; -.
DR PDBsum; 6IMB; -.
DR PDBsum; 6IMD; -.
DR PDBsum; 6IMI; -.
DR PDBsum; 6IMO; -.
DR PDBsum; 6IMR; -.
DR PDBsum; 6IMT; -.
DR PDBsum; 6IND; -.
DR PDBsum; 6INK; -.
DR PDBsum; 6INM; -.
DR PDBsum; 6KJZ; -.
DR PDBsum; 6KK0; -.
DR PDBsum; 6LRM; -.
DR PDBsum; 6NJH; -.
DR PDBsum; 6NJI; -.
DR PDBsum; 6NJJ; -.
DR PDBsum; 6RCW; -.
DR PDBsum; 6ZBA; -.
DR PDBsum; 7A8Q; -.
DR PDBsum; 7A9V; -.
DR PDBsum; 7AAG; -.
DR PDBsum; 7AB9; -.
DR PDBsum; 7ABD; -.
DR PDBsum; 7ABE; -.
DR PDBsum; 7ABJ; -.
DR PDBsum; 7AY6; -.
DR PDBsum; 7B9H; -.
DR PDBsum; 7CBJ; -.
DR PDBsum; 7CBQ; -.
DR PDBsum; 7F2K; -.
DR PDBsum; 7F2L; -.
DR PDBsum; 7F2M; -.
DR PDBsum; 7W4X; -.
DR PDBsum; 7W4Y; -.
DR PDBsum; 7XAA; -.
DR PDBsum; 7XAB; -.
DR PDBsum; 7XBB; -.
DR PDBsum; 7YQF; -.
DR PDBsum; 7YSX; -.
DR PDBsum; 8K4C; -.
DR PDBsum; 8K4H; -.
DR PDBsum; 8W4Q; -.
DR PDBsum; 8W4R; -.
DR AlphaFoldDB; Q08499; -.
DR SMR; Q08499; -.
DR BioGRID; 111170; 71.
DR CORUM; Q08499; -.
DR DIP; DIP-41115N; -.
DR IntAct; Q08499; 31.
DR MINT; Q08499; -.
DR STRING; 9606.ENSP00000345502; -.
DR BindingDB; Q08499; -.
DR ChEMBL; CHEMBL288; -.
DR DrugBank; DB06842; (4R)-4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one.
DR DrugBank; DB04149; (R)-Rolipram.
DR DrugBank; DB03606; (S)-Rolipram.
DR DrugBank; DB03183; 1-(4-Aminophenyl)-3,5-Dimethyl-1h-Pyrazole-4-Carboxylic Acid Ethyl Ester.
DR DrugBank; DB04469; 1-(4-Methoxyphenyl)-3,5-Dimethyl-1h-Pyrazole-4-Carboxylic Acid Ethyl Ester.
DR DrugBank; DB02676; 2-[3-(2-Hydroxy-1,1-Dihydroxymethyl-Ethylamino)-Propylamino]-2-Hydroxymethyl-Propane-1,3-Diol.
DR DrugBank; DB01959; 3,5-Dimethyl-1-(3-Nitrophenyl)-1h-Pyrazole-4-Carboxylic Acid Ethyl Ester.
DR DrugBank; DB07051; 3,5-DIMETHYL-1-PHENYL-1H-PYRAZOLE-4-CARBOXYLIC ACID ETHYL ESTER.
DR DrugBank; DB04271; 3,5-Dimethyl-1h-Pyrazole-4-Carboxylic Acid Ethyl Ester.
DR DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine.
DR DrugBank; DB08299; 4-[8-(3-nitrophenyl)-1,7-naphthyridin-6-yl]benzoic acid.
DR DrugBank; DB00131; Adenosine phosphate.
DR DrugBank; DB01427; Amrinone.
DR DrugBank; DB00201; Caffeine.
DR DrugBank; DB03849; Cilomilast.
DR DrugBank; DB05219; Crisaborole.
DR DrugBank; DB00651; Dyphylline.
DR DrugBank; DB06246; Exisulind.
DR DrugBank; DB05266; Ibudilast.
DR DrugBank; DB01088; Iloprost.
DR DrugBank; DB01113; Papaverine.
DR DrugBank; DB01791; Piclamilast.
DR DrugBank; DB01656; Roflumilast.
DR DrugBank; DB01954; Rolipram.
DR DrugBank; DB05298; Tetomilast.
DR DrugBank; DB09283; Trapidil.
DR DrugBank; DB02918; Zardaverine.
DR DrugCentral; Q08499; -.
DR GuidetoPHARMACOLOGY; 1303; -.
DR GlyGen; Q08499; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q08499; -.
DR PhosphoSitePlus; Q08499; -.
DR BioMuta; PDE4D; -.
DR DMDM; 12644392; -.
DR EPD; Q08499; -.
DR jPOST; Q08499; -.
DR MassIVE; Q08499; -.
DR MaxQB; Q08499; -.
DR PaxDb; 9606-ENSP00000345502; -.
DR PeptideAtlas; Q08499; -.
DR ProteomicsDB; 58620; -. [Q08499-1]
DR ProteomicsDB; 58621; -. [Q08499-10]
DR ProteomicsDB; 58622; -. [Q08499-11]
DR ProteomicsDB; 58623; -. [Q08499-12]
DR ProteomicsDB; 58624; -. [Q08499-2]
DR ProteomicsDB; 58625; -. [Q08499-3]
DR ProteomicsDB; 58626; -. [Q08499-4]
DR ProteomicsDB; 58627; -. [Q08499-5]
DR ProteomicsDB; 58628; -. [Q08499-6]
DR ProteomicsDB; 58629; -. [Q08499-7]
DR ProteomicsDB; 58630; -. [Q08499-8]
DR ProteomicsDB; 58631; -. [Q08499-9]
DR Pumba; Q08499; -.
DR Antibodypedia; 23607; 588 antibodies from 39 providers.
DR DNASU; 5144; -.
DR Ensembl; ENST00000309641.10; ENSP00000308485.6; ENSG00000113448.21. [Q08499-7]
DR Ensembl; ENST00000317118.12; ENSP00000321739.8; ENSG00000113448.21. [Q08499-8]
DR Ensembl; ENST00000340635.11; ENSP00000345502.6; ENSG00000113448.21. [Q08499-1]
DR Ensembl; ENST00000358923.10; ENSP00000351800.6; ENSG00000113448.21. [Q08499-5]
DR Ensembl; ENST00000360047.9; ENSP00000353152.5; ENSG00000113448.21. [Q08499-2]
DR Ensembl; ENST00000405755.6; ENSP00000384806.2; ENSG00000113448.21. [Q08499-9]
DR Ensembl; ENST00000502484.6; ENSP00000423094.2; ENSG00000113448.21. [Q08499-11]
DR Ensembl; ENST00000502575.1; ENSP00000425917.1; ENSG00000113448.21. [Q08499-12]
DR Ensembl; ENST00000503258.5; ENSP00000425605.1; ENSG00000113448.21. [Q08499-10]
DR Ensembl; ENST00000507116.6; ENSP00000424852.1; ENSG00000113448.21. [Q08499-6]
DR GeneID; 5144; -.
DR KEGG; hsa:5144; -.
DR MANE-Select; ENST00000340635.11; ENSP00000345502.6; NM_001104631.2; NP_001098101.1.
DR UCSC; uc003jrs.4; human. [Q08499-1]
DR AGR; HGNC:8783; -.
DR CTD; 5144; -.
DR DisGeNET; 5144; -.
DR GeneCards; PDE4D; -.
DR HGNC; HGNC:8783; PDE4D.
DR HPA; ENSG00000113448; Tissue enhanced (bone).
DR MalaCards; PDE4D; -.
DR MIM; 600129; gene.
DR MIM; 614613; phenotype.
DR neXtProt; NX_Q08499; -.
DR OpenTargets; ENSG00000113448; -.
DR Orphanet; 950; Acrodysostosis.
DR Orphanet; 439822; PDE4D haploinsufficiency syndrome.
DR PharmGKB; PA33130; -.
DR VEuPathDB; HostDB:ENSG00000113448; -.
DR eggNOG; KOG3689; Eukaryota.
DR GeneTree; ENSGT00940000155674; -.
DR HOGENOM; CLU_005940_5_2_1; -.
DR InParanoid; Q08499; -.
DR OMA; FNTDEGG; -.
DR OrthoDB; 240889at2759; -.
DR PhylomeDB; Q08499; -.
DR TreeFam; TF314638; -.
DR BRENDA; 3.1.4.53; 2681.
DR PathwayCommons; Q08499; -.
DR Reactome; R-HSA-180024; DARPP-32 events.
DR Reactome; R-HSA-418555; G alpha (s) signalling events.
DR SABIO-RK; Q08499; -.
DR SignaLink; Q08499; -.
DR SIGNOR; Q08499; -.
DR UniPathway; UPA00762; UER00747.
DR BioGRID-ORCS; 5144; 19 hits in 1159 CRISPR screens.
DR ChiTaRS; PDE4D; human.
DR EvolutionaryTrace; Q08499; -.
DR GeneWiki; PDE4D; -.
DR GenomeRNAi; 5144; -.
DR Pharos; Q08499; Tclin.
DR PRO; PR:Q08499; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q08499; Protein.
DR Bgee; ENSG00000113448; Expressed in gluteal muscle and 202 other cell types or tissues.
DR ExpressionAtlas; Q08499; baseline and differential.
DR Genevisible; Q08499; HS.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0034704; C:calcium channel complex; IDA:BHF-UCL.
DR GO; GO:0005813; C:centrosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:0016020; C:membrane; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0005891; C:voltage-gated calcium channel complex; ISS:BHF-UCL.
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; NAS:UniProtKB.
DR GO; GO:0051117; F:ATPase binding; IPI:BHF-UCL.
DR GO; GO:0031698; F:beta-2 adrenergic receptor binding; ISS:BHF-UCL.
DR GO; GO:0005246; F:calcium channel regulator activity; ISS:BHF-UCL.
DR GO; GO:0030552; F:cAMP binding; IDA:BHF-UCL.
DR GO; GO:0019899; F:enzyme binding; ISS:BHF-UCL.
DR GO; GO:1901363; F:heterocyclic compound binding; IPI:BHF-UCL.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL.
DR GO; GO:0030545; F:signaling receptor regulator activity; ISS:BHF-UCL.
DR GO; GO:0044325; F:transmembrane transporter binding; IPI:BHF-UCL.
DR GO; GO:0071875; P:adrenergic receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0006198; P:cAMP catabolic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0019933; P:cAMP-mediated signaling; NAS:BHF-UCL.
DR GO; GO:0071320; P:cellular response to cAMP; IDA:BHF-UCL.
DR GO; GO:0071872; P:cellular response to epinephrine stimulus; IDA:BHF-UCL.
DR GO; GO:0061028; P:establishment of endothelial barrier; ISS:UniProtKB.
DR GO; GO:0043951; P:negative regulation of cAMP-mediated signaling; IDA:BHF-UCL.
DR GO; GO:0045822; P:negative regulation of heart contraction; ISS:BHF-UCL.
DR GO; GO:0033137; P:negative regulation of peptidyl-serine phosphorylation; ISS:BHF-UCL.
DR GO; GO:1901898; P:negative regulation of relaxation of cardiac muscle; ISS:BHF-UCL.
DR GO; GO:0010460; P:positive regulation of heart rate; ISS:BHF-UCL.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; IMP:BHF-UCL.
DR GO; GO:0032754; P:positive regulation of interleukin-5 production; IMP:BHF-UCL.
DR GO; GO:0032729; P:positive regulation of type II interferon production; IMP:BHF-UCL.
DR GO; GO:1902514; P:regulation of calcium ion transmembrane transport via high voltage-gated calcium channel; ISS:BHF-UCL.
DR GO; GO:0086004; P:regulation of cardiac muscle cell contraction; ISS:BHF-UCL.
DR GO; GO:1901844; P:regulation of cell communication by electrical coupling involved in cardiac conduction; IMP:BHF-UCL.
DR GO; GO:0002027; P:regulation of heart rate; ISS:BHF-UCL.
DR GO; GO:0010880; P:regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum; ISS:BHF-UCL.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IMP:BHF-UCL.
DR Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1.
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 PANTHER; PTHR11347:SF91; CAMP-SPECIFIC 3',5'-CYCLIC PHOSPHODIESTERASE 4D; 1.
DR PANTHER; PTHR11347; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1.
DR Pfam; PF18100; PDE4_UCR; 1.
DR Pfam; PF00233; PDEase_I; 1.
DR PRINTS; PR00387; PDIESTERASE1.
DR SUPFAM; SSF109604; HD-domain/PDEase-like; 1.
DR PROSITE; PS00126; PDEASE_I_1; 1.
DR PROSITE; PS51845; PDEASE_I_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; cAMP; Cell membrane; Cytoplasm;
KW Cytoskeleton; Disease variant; Hydrolase; Isopeptide bond; Manganese;
KW Membrane; Metal-binding; Phosphoprotein; Reference proteome;
KW Ubl conjugation; Zinc.
FT CHAIN 1..809
FT /note="3',5'-cyclic-AMP phosphodiesterase 4D"
FT /id="PRO_0000198814"
FT DOMAIN 386..715
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 1..107
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 343..364
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 710..729
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 739..809
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 53..91
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 345..362
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 758..777
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 778..798
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 462
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 462
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:17582435,
FT ECO:0007744|PDB:2PW3"
FT BINDING 462
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7"
FT BINDING 466
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036,
FT ECO:0000269|PubMed:17582435, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7, ECO:0007744|PDB:1TBB,
FT ECO:0007744|PDB:1XOM, ECO:0007744|PDB:1XON,
FT ECO:0007744|PDB:1XOQ, ECO:0007744|PDB:2PW3"
FT BINDING 502
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036,
FT ECO:0000269|PubMed:17582435, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7, ECO:0007744|PDB:1TBB,
FT ECO:0007744|PDB:1XOM, ECO:0007744|PDB:1XON,
FT ECO:0007744|PDB:1XOQ, ECO:0007744|PDB:1XOR,
FT ECO:0007744|PDB:2PW3"
FT BINDING 503
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7"
FT BINDING 503
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:15260978,
FT ECO:0000269|PubMed:15576036, ECO:0007744|PDB:1TB7,
FT ECO:0007744|PDB:1XOM, ECO:0007744|PDB:1XON,
FT ECO:0007744|PDB:1XOQ, ECO:0007744|PDB:1XOR"
FT BINDING 503
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /evidence="ECO:0000250|UniProtKB:Q07343"
FT BINDING 503
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036,
FT ECO:0007744|PDB:1PTW, ECO:0007744|PDB:1TB7,
FT ECO:0007744|PDB:1TBB, ECO:0007744|PDB:1XOM,
FT ECO:0007744|PDB:1XON, ECO:0007744|PDB:1XOQ,
FT ECO:0007744|PDB:1XOR"
FT BINDING 503
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0007744|PDB:1PTW"
FT BINDING 620
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7"
FT BINDING 620
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036,
FT ECO:0000269|PubMed:17582435, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7, ECO:0007744|PDB:1TBB,
FT ECO:0007744|PDB:1XOM, ECO:0007744|PDB:1XON,
FT ECO:0007744|PDB:1XOQ, ECO:0007744|PDB:1XOR,
FT ECO:0007744|PDB:2PW3"
FT BINDING 623
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7"
FT BINDING 671
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:17582435,
FT ECO:0007744|PDB:2PW3"
FT BINDING 671
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0000269|PubMed:15260978, ECO:0007744|PDB:1PTW,
FT ECO:0007744|PDB:1TB7"
FT BINDING 674
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:17582435,
FT ECO:0007744|PDB:2PW3"
FT BINDING 674
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:14609333,
FT ECO:0007744|PDB:1PTW"
FT MOD_RES 142
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P14270"
FT MOD_RES 299
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 301
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692"
FT MOD_RES 348
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 375
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 387
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT VAR_SEQ 1..302
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:8797812,
FT ECO:0000303|PubMed:9371713"
FT /id="VSP_004580"
FT VAR_SEQ 1..291
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:12834813,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_012383"
FT VAR_SEQ 1..269
FT /note="MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQYPLRQPQFRLLH
FT PHHHLPPPPPPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSD
FT TERYLYCRAMDRTSYAVETGHRPGLKKSRMSWPSSFQGLRRFDVDNGTSAGRSPLDPMT
FT SPGSGLILQANFVHSQRRESFLYRSDSDYDLSPKSMSRNSSIASDIHGDDLIVTPFAQV
FT LASLRTVRNNFAALTNLQDRAPSKRSPMCNQPSINKATIT -> MKEQPSCAGTGHPMA
FT GYGRMAPFELASGPVKRLRTESPFPCLFA (in isoform 1)"
FT /evidence="ECO:0000303|PubMed:8797812,
FT ECO:0000303|PubMed:9371713"
FT /id="VSP_004579"
FT VAR_SEQ 1..205
FT /note="Missing (in isoform 10)"
FT /evidence="ECO:0000303|PubMed:8125310,
FT ECO:0000303|PubMed:9371713"
FT /id="VSP_004578"
FT VAR_SEQ 1..152
FT /note="MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQYPLRQPQFRLLH
FT PHHHLPPPPPPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSD
FT TERYLYCRAMDRTSYAVETGHRPGLKKSRMSWPSSFQGLRR -> MMHVNNFPFRRHSW
FT IC (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:8413254,
FT ECO:0000303|PubMed:9371713"
FT /id="VSP_004577"
FT VAR_SEQ 1..152
FT /note="MEAEGSSAPARAGSGEGSDSAGGATLKAPKHLWRHEQHHQYPLRQPQFRLLH
FT PHHHLPPPPPPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSD
FT TERYLYCRAMDRTSYAVETGHRPGLKKSRMSWPSSFQGLRR -> MAQQTSPDTLTVPE
FT VDNPHCPNPWLNEDLVKSLRENLLQHEKSKTARKSVSPKLSPVISPRNSPRLLRRMLLS
FT SNIPKQRRFTVAHTC (in isoform 5, isoform N3 and isoform 12)"
FT /evidence="ECO:0000303|PubMed:10913353,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:9371713,
FT ECO:0000303|Ref.9"
FT /id="VSP_012384"
FT VAR_SEQ 1..130
FT /note="Missing (in isoform 9)"
FT /evidence="ECO:0000303|PubMed:12834813,
FT ECO:0000303|PubMed:14517540"
FT /id="VSP_012385"
FT VAR_SEQ 1..122
FT /note="Missing (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:12834813"
FT /id="VSP_012386"
FT VAR_SEQ 1..61
FT /note="Missing (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:12834813,
FT ECO:0000303|PubMed:14517540"
FT /id="VSP_012387"
FT VAR_SEQ 62..152
FT /note="PPSPQPQPQCPLQPPPPPPLPPPPPPPGAARGRYASSGATGRVRHRGYSDTE
FT RYLYCRAMDRTSYAVETGHRPGLKKSRMSWPSSFQGLRR -> MKRNTCDLLSRSKSAS
FT EETLHSSNEEEDPFRGMEPYLVRRLSCRNIQLPPLAFRQLEQADLKSESENIQRPTSLP
FT LKILPLIAITSAESSG (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:12834813,
FT ECO:0000303|PubMed:14517540"
FT /id="VSP_012388"
FT VAR_SEQ 123..152
FT /note="RTSYAVETGHRPGLKKSRMSWPSSFQGLRR -> MAFVWDPLGATVPGPSTR
FT AKSRLRFSKSYS (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:12834813"
FT /id="VSP_012389"
FT VAR_SEQ 131..152
FT /note="GHRPGLKKSRMSWPSSFQGLRR -> MSIIMKPRSRSTSSLRTAEAVC (in
FT isoform 9)"
FT /evidence="ECO:0000303|PubMed:12834813,
FT ECO:0000303|PubMed:14517540"
FT /id="VSP_012390"
FT VAR_SEQ 270..283
FT /note="EEAYQKLASETLEE -> GSWMELNPYTLLDM (in isoform 12)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.9"
FT /id="VSP_023326"
FT VAR_SEQ 270..279
FT /note="EEAYQKLASE -> GLYNGIIAFL (in isoform N3)"
FT /evidence="ECO:0000303|PubMed:10913353"
FT /id="VSP_012391"
FT VAR_SEQ 280..809
FT /note="Missing (in isoform N3)"
FT /evidence="ECO:0000303|PubMed:10913353"
FT /id="VSP_012392"
FT VAR_SEQ 284..809
FT /note="Missing (in isoform 12)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.9"
FT /id="VSP_023327"
FT VAR_SEQ 292..306
FT /note="ETLQTRHSVSEMASN -> MPEANYLLSVSWGYI (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:12834813,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_012393"
FT VARIANT 190
FT /note="S -> A (in ACRDYS2; dbSNP:rs397514466)"
FT /evidence="ECO:0000269|PubMed:22464250"
FT /id="VAR_068242"
FT VARIANT 225
FT /note="P -> T (in ACRDYS2; dbSNP:rs397514464)"
FT /evidence="ECO:0000269|PubMed:22464250,
FT ECO:0000269|PubMed:23033274"
FT /id="VAR_068243"
FT VARIANT 226
FT /note="F -> S (in ACRDYS2; dbSNP:rs397514465)"
FT /evidence="ECO:0000269|PubMed:22464250"
FT /id="VAR_068244"
FT VARIANT 227
FT /note="A -> S (in ACRDYS2)"
FT /evidence="ECO:0000269|PubMed:23043190"
FT /id="VAR_069448"
FT VARIANT 228
FT /note="Q -> E (in ACRDYS2; dbSNP:rs397514468)"
FT /evidence="ECO:0000269|PubMed:22464252"
FT /id="VAR_069449"
FT VARIANT 301
FT /note="S -> T (in ACRDYS2)"
FT /evidence="ECO:0000269|PubMed:23033274"
FT /id="VAR_069450"
FT VARIANT 304
FT /note="A -> V (in ACRDYS2; dbSNP:rs397515433)"
FT /evidence="ECO:0000269|PubMed:23033274"
FT /id="VAR_069451"
FT VARIANT 329
FT /note="V -> A (in ACRDYS2)"
FT /evidence="ECO:0000269|PubMed:23033274"
FT /id="VAR_069452"
FT VARIANT 587
FT /note="T -> P (in ACRDYS2; dbSNP:rs397514467)"
FT /evidence="ECO:0000269|PubMed:22464250"
FT /id="VAR_068245"
FT VARIANT 590
FT /note="E -> A (in ACRDYS2)"
FT /evidence="ECO:0000269|PubMed:22464252,
FT ECO:0000269|PubMed:23043190"
FT /id="VAR_069453"
FT VARIANT 673
FT /note="G -> D (in ACRDYS2; dbSNP:rs397514469)"
FT /evidence="ECO:0000269|PubMed:22464252"
FT /id="VAR_069454"
FT VARIANT 678
FT /note="I -> T (in ACRDYS2; dbSNP:rs587777188)"
FT /evidence="ECO:0000269|PubMed:23033274"
FT /id="VAR_069455"
FT MUTAGEN 503
FT /note="D->N: Decreased 3',5'-cyclic-AMP phosphodiesterase
FT activity. Loss of Mg2(+)-binding."
FT /evidence="ECO:0000269|PubMed:17582435"
FT MUTAGEN 527
FT /note="D->R: Abolishes homodimerization."
FT /evidence="ECO:0000269|PubMed:12387865"
FT MUTAGEN 563
FT /note="R->D: Abolishes homodimerization."
FT /evidence="ECO:0000269|PubMed:12387865"
FT CONFLICT 510
FT /note="S -> F (in Ref. 10; AAH36319)"
FT /evidence="ECO:0000305"
FT CONFLICT 549
FT /note="D -> G (in Ref. 6; AAN10119)"
FT /evidence="ECO:0000305"
FT CONFLICT 644
FT /note="R -> P (in Ref. 2)"
FT /evidence="ECO:0000305"
FT CONFLICT 769
FT /note="C -> R (in Ref. 3; AAA97890/AAA97891/AAA97892)"
FT /evidence="ECO:0000305"
FT STRAND 256..259
FT /evidence="ECO:0007829|PDB:1E9K"
FT HELIX 261..265
FT /evidence="ECO:0007829|PDB:1E9K"
FT TURN 266..271
FT /evidence="ECO:0007829|PDB:1E9K"
FT STRAND 272..274
FT /evidence="ECO:0007829|PDB:1E9K"
FT HELIX 275..280
FT /evidence="ECO:0007829|PDB:1E9K"
FT HELIX 328..336
FT /evidence="ECO:0007829|PDB:3G4G"
FT STRAND 383..386
FT /evidence="ECO:0007829|PDB:1OYN"
FT HELIX 389..397
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 398..400
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 408..414
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 419..430
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 433..436
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 441..453
FT /evidence="ECO:0007829|PDB:1Y2K"
FT STRAND 460..463
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 464..478
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 481..483
FT /evidence="ECO:0007829|PDB:1Y2K"
FT TURN 484..486
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 489..501
FT /evidence="ECO:0007829|PDB:1Y2K"
FT TURN 502..505
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 511..516
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 520..525
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 530..541
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 542..544
FT /evidence="ECO:0007829|PDB:1Y2K"
FT TURN 545..547
FT /evidence="ECO:0007829|PDB:5K32"
FT TURN 550..553
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 556..571
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 575..577
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 578..590
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 595..597
FT /evidence="ECO:0007829|PDB:7ABE"
FT STRAND 598..600
FT /evidence="ECO:0007829|PDB:6LRM"
FT HELIX 605..620
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 623..625
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 628..652
FT /evidence="ECO:0007829|PDB:1Y2K"
FT TURN 658..660
FT /evidence="ECO:0007829|PDB:3SL3"
FT TURN 662..664
FT /evidence="ECO:0007829|PDB:6FW3"
FT HELIX 667..677
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 679..689
FT /evidence="ECO:0007829|PDB:1Y2K"
FT TURN 690..694
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 695..710
FT /evidence="ECO:0007829|PDB:1Y2K"
FT HELIX 730..734
FT /evidence="ECO:0007829|PDB:6BOJ"
FT TURN 735..738
FT /evidence="ECO:0007829|PDB:3G58"
FT MOD_RES Q08499-2:54
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:15131123"
FT MOD_RES Q08499-6:59
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES Q08499-6:63
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES Q08499-7:59
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES Q08499-7:63
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES Q08499-12:59
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES Q08499-12:63
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
SQ 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
//
