PDE8A_HUMAN
ID PDE8A_HUMAN Reviewed; 829 AA.
AC O60658; B3KXE6; H0YMZ7; Q6P9H3; Q969I1; Q96PC9; Q96PD0; Q96PD1; Q96T71;
AC Q9UMB7; Q9UMC3;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 19-SEP-2002, sequence version 2.
DT 03-AUG-2022, entry version 208.
DE RecName: Full=High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A;
DE EC=3.1.4.53 {ECO:0000250|UniProtKB:O95263};
GN Name=PDE8A;
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 1; 2; 3; 4 AND 5).
RC TISSUE=Testis;
RX PubMed=11738832; DOI=10.1016/s0378-1119(01)00783-1;
RA Wang P., Wu P., Egan R.W., Billah M.M.;
RT "Human phosphodiesterase 8A splice variants: cloning, gene organization,
RT and tissue distribution.";
RL Gene 280:183-194(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11371644; DOI=10.1073/pnas.101131098;
RA Glavas N.A., Ostenson C., Schaefer J.B., Vasta V., Beavo J.A.;
RT "T cell activation up-regulates cyclic nucleotide phosphodiesterases 8A1
RT and 7A3.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:6319-6324(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 6), NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 381-829 (ISOFORM 1), AND VARIANT GLY-112.
RC TISSUE=Hippocampus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J.,
RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E.,
RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B.,
RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R.,
RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B.,
RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S.,
RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human chromosome
RT 15.";
RL Nature 440:671-675(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT GLY-112.
RC TISSUE=Liver, and Placenta;
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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 117-829 (ISOFORMS 1 AND 2).
RX PubMed=9618252; DOI=10.1006/bbrc.1998.8684;
RA Fisher D.A., Smith J.F., Pillar J.S., St Denis S.H., Cheng J.B.;
RT "Isolation and characterization of PDE8A, a novel human cAMP-specific
RT phosphodiesterase.";
RL Biochem. Biophys. Res. Commun. 246:570-577(1998).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 554-829.
RG The European IMAGE consortium;
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20 AND SER-457, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-457, AND IDENTIFICATION BY
RP 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 [12]
RP PHOSPHORYLATION AT SER-359.
RX PubMed=22673573; DOI=10.1016/j.febslet.2012.04.033;
RA Brown K.M., Lee L.C., Findlay J.E., Day J.P., Baillie G.S.;
RT "Cyclic AMP-specific phosphodiesterase, PDE8A1, is activated by protein
RT kinase A-mediated phosphorylation.";
RL FEBS Lett. 586:1631-1637(2012).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-20 AND SER-457, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
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 [14]
RP FUNCTION, INTERACTION WITH RAF1, MUTAGENESIS OF 454-ARG-ARG-455 AND
RP 460-GLU-LYS-461, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23509299; DOI=10.1073/pnas.1303004110;
RA Brown K.M., Day J.P., Huston E., Zimmermann B., Hampel K., Christian F.,
RA Romano D., Terhzaz S., Lee L.C., Willis M.J., Morton D.B., Beavo J.A.,
RA Shimizu-Albergine M., Davies S.A., Kolch W., Houslay M.D., Baillie G.S.;
RT "Phosphodiesterase-8A binds to and regulates Raf-1 kinase.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:E1533-E1542(2013).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 482-819 IN COMPLEX WITH METAL
RP IONS AND THE INHIBITOR IBMX, FUNCTION, COFACTOR, AND MUTAGENESIS OF
RP TYR-748.
RX PubMed=18983167; DOI=10.1021/bi801487x;
RA Wang H., Yan Z., Yang S., Cai J., Robinson H., Ke H.;
RT "Kinetic and structural studies of phosphodiesterase-8A and implication on
RT the inhibitor selectivity.";
RL Biochemistry 47:12760-12768(2008).
CC -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key
CC regulator of many important physiological processes (PubMed:18983167).
CC May be involved in maintaining basal levels of the cyclic nucleotide
CC and/or in the cAMP regulation of germ cell development
CC (PubMed:18983167). Binding to RAF1 reduces RAF1 'Ser-259' inhibitory-
CC phosphorylation and stimulates RAF1-dependent EGF-activated ERK-
CC signaling (PubMed:23509299). Protects against cell death induced by
CC hydrogen peroxide and staurosporine (PubMed:23509299).
CC {ECO:0000269|PubMed:18983167, ECO:0000269|PubMed:23509299}.
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:0000250|UniProtKB:O95263};
CC -!- COFACTOR:
CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
CC Evidence={ECO:0000269|PubMed:18983167};
CC Note=Binds 2 divalent metal cations per subunit. Site 1 may
CC preferentially bind zinc ions, while site 2 has a preference for
CC magnesium and/or manganese ions. {ECO:0000269|PubMed:18983167};
CC -!- ACTIVITY REGULATION: Inhibited by dipyridimole. Insensitive to
CC selective PDE inhibitors including rolipram and zaprinast as well as to
CC the non-selective inhibitor, IBMX. Unaffected by cGMP.
CC {ECO:0000250|UniProtKB:O95263}.
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from
CC 3',5'-cyclic AMP: step 1/1.
CC -!- SUBUNIT: Interacts with RAF1. The interaction promotes RAF1 activity.
CC {ECO:0000269|PubMed:23509299}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=PDE8A1;
CC IsoId=O60658-1; Sequence=Displayed;
CC Name=2; Synonyms=PDE8A2;
CC IsoId=O60658-2; Sequence=VSP_004597;
CC Name=3; Synonyms=PDE8A3;
CC IsoId=O60658-3; Sequence=VSP_041675, VSP_041677;
CC Name=4; Synonyms=PDE8A4;
CC IsoId=O60658-4; Sequence=VSP_041674, VSP_041676;
CC Name=5; Synonyms=PDE8A5;
CC IsoId=O60658-5; Sequence=VSP_041678, VSP_041679;
CC Name=6;
CC IsoId=O60658-6; Sequence=VSP_046017;
CC -!- TISSUE SPECIFICITY: Expressed in most tissues except thymus and
CC peripheral blood leukocytes. Highest levels in testis, ovary, small
CC intestine and colon.
CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two
CC putative divalent metal sites and an N-terminal regulatory domain.
CC -!- PTM: Phosphorylated at Ser-359 by PKA under elevated cAMP conditions,
CC this enhances catalytic activity. {ECO:0000269|PubMed:22673573}.
CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 4]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE8 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAL18612.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305};
CC Sequence=AAL18613.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305};
CC Sequence=AAL18614.1; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305};
CC Sequence=BAG54458.1; Type=Miscellaneous discrepancy; Note=Intron retention.; Evidence={ECO:0000305};
CC Sequence=EAX01967.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF388183; AAL18610.1; -; mRNA.
DR EMBL; AF388184; AAL18611.1; -; mRNA.
DR EMBL; AF388185; AAL18612.1; ALT_SEQ; mRNA.
DR EMBL; AF388186; AAL18613.1; ALT_SEQ; mRNA.
DR EMBL; AF388187; AAL18614.1; ALT_SEQ; mRNA.
DR EMBL; AF332653; AAK57641.1; -; mRNA.
DR EMBL; AK074280; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AK127232; BAG54458.1; ALT_SEQ; mRNA.
DR EMBL; AC027078; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC087468; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471101; EAX01967.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC060762; AAH60762.1; -; mRNA.
DR EMBL; BC075822; AAH75822.1; -; mRNA.
DR EMBL; AF056490; AAC39763.1; -; mRNA.
DR EMBL; AL109687; CAB52020.1; -; mRNA.
DR EMBL; AL109778; CAB52432.1; -; mRNA.
DR CCDS; CCDS10336.1; -. [O60658-1]
DR CCDS; CCDS10337.1; -. [O60658-2]
DR CCDS; CCDS58397.1; -. [O60658-6]
DR PIR; JW0088; JW0088.
DR RefSeq; NP_001230066.1; NM_001243137.1. [O60658-6]
DR RefSeq; NP_002596.1; NM_002605.2. [O60658-1]
DR RefSeq; NP_775656.1; NM_173454.1. [O60658-2]
DR RefSeq; XP_016877800.1; XM_017022311.1.
DR PDB; 3ECM; X-ray; 1.90 A; A=482-819.
DR PDB; 3ECN; X-ray; 2.10 A; A/B=482-819.
DR PDB; 7CWA; X-ray; 2.80 A; A=482-819.
DR PDB; 7CWF; X-ray; 2.80 A; A=482-819.
DR PDB; 7CWG; X-ray; 2.80 A; A=482-819.
DR PDBsum; 3ECM; -.
DR PDBsum; 3ECN; -.
DR PDBsum; 7CWA; -.
DR PDBsum; 7CWF; -.
DR PDBsum; 7CWG; -.
DR AlphaFoldDB; O60658; -.
DR SMR; O60658; -.
DR BioGRID; 111177; 20.
DR IntAct; O60658; 6.
DR STRING; 9606.ENSP00000311453; -.
DR BindingDB; O60658; -.
DR ChEMBL; CHEMBL4640; -.
DR DrugBank; DB07954; 3-isobutyl-1-methyl-7H-xanthine.
DR DrugBank; DB00201; Caffeine.
DR DrugBank; DB09283; Trapidil.
DR DrugCentral; O60658; -.
DR GuidetoPHARMACOLOGY; 1307; -.
DR iPTMnet; O60658; -.
DR PhosphoSitePlus; O60658; -.
DR BioMuta; PDE8A; -.
DR EPD; O60658; -.
DR jPOST; O60658; -.
DR MassIVE; O60658; -.
DR MaxQB; O60658; -.
DR PaxDb; O60658; -.
DR PeptideAtlas; O60658; -.
DR PRIDE; O60658; -.
DR ProteomicsDB; 40410; -.
DR ProteomicsDB; 49499; -. [O60658-1]
DR ProteomicsDB; 49500; -. [O60658-2]
DR ProteomicsDB; 49501; -. [O60658-3]
DR ProteomicsDB; 49502; -. [O60658-4]
DR ProteomicsDB; 49503; -. [O60658-5]
DR Antibodypedia; 679; 289 antibodies from 33 providers.
DR DNASU; 5151; -.
DR Ensembl; ENST00000310298.8; ENSP00000311453.4; ENSG00000073417.15. [O60658-1]
DR Ensembl; ENST00000339708.9; ENSP00000340679.5; ENSG00000073417.15. [O60658-2]
DR Ensembl; ENST00000394553.6; ENSP00000378056.1; ENSG00000073417.15. [O60658-1]
DR Ensembl; ENST00000478717.5; ENSP00000432309.1; ENSG00000073417.15. [O60658-4]
DR Ensembl; ENST00000557957.5; ENSP00000453808.1; ENSG00000073417.15. [O60658-6]
DR GeneID; 5151; -.
DR KEGG; hsa:5151; -.
DR MANE-Select; ENST00000394553.6; ENSP00000378056.1; NM_002605.3; NP_002596.1.
DR UCSC; uc002blh.4; human. [O60658-1]
DR CTD; 5151; -.
DR DisGeNET; 5151; -.
DR GeneCards; PDE8A; -.
DR HGNC; HGNC:8793; PDE8A.
DR HPA; ENSG00000073417; Low tissue specificity.
DR MIM; 602972; gene.
DR neXtProt; NX_O60658; -.
DR OpenTargets; ENSG00000073417; -.
DR PharmGKB; PA33141; -.
DR VEuPathDB; HostDB:ENSG00000073417; -.
DR eggNOG; KOG1229; Eukaryota.
DR GeneTree; ENSGT00940000156422; -.
DR HOGENOM; CLU_005940_4_2_1; -.
DR OMA; HWDFDIF; -.
DR OrthoDB; 904682at2759; -.
DR PhylomeDB; O60658; -.
DR TreeFam; TF314638; -.
DR BRENDA; 3.1.4.53; 2681.
DR PathwayCommons; O60658; -.
DR Reactome; R-HSA-418555; G alpha (s) signalling events.
DR SignaLink; O60658; -.
DR UniPathway; UPA00762; UER00747.
DR BioGRID-ORCS; 5151; 7 hits in 1080 CRISPR screens.
DR ChiTaRS; PDE8A; human.
DR EvolutionaryTrace; O60658; -.
DR GeneWiki; PDE8A; -.
DR GenomeRNAi; 5151; -.
DR Pharos; O60658; Tclin.
DR PRO; PR:O60658; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; O60658; protein.
DR Bgee; ENSG00000073417; Expressed in corpus callosum and 209 other tissues.
DR ExpressionAtlas; O60658; baseline and differential.
DR Genevisible; O60658; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IMP:UniProtKB.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006198; P:cAMP catabolic process; IEA:UniProtKB-UniPathway.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IMP:UniProtKB.
DR GO; GO:0060548; P:negative regulation of cell death; IMP:UniProtKB.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; IEA:InterPro.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR CDD; cd00077; HDc; 1.
DR CDD; cd00130; PAS; 1.
DR Gene3D; 1.10.1300.10; -; 1.
DR InterPro; IPR003607; HD/PDEase_dom.
DR InterPro; IPR000014; PAS.
DR InterPro; IPR035965; PAS-like_dom_sf.
DR InterPro; IPR013767; PAS_fold.
DR InterPro; IPR023088; PDEase.
DR InterPro; IPR002073; PDEase_catalytic_dom.
DR InterPro; IPR036971; PDEase_catalytic_dom_sf.
DR InterPro; IPR023174; PDEase_CS.
DR Pfam; PF00989; PAS; 1.
DR Pfam; PF00233; PDEase_I; 1.
DR PRINTS; PR00387; PDIESTERASE1.
DR SMART; SM00471; HDc; 1.
DR SUPFAM; SSF55785; SSF55785; 1.
DR TIGRFAMs; TIGR00229; sensory_box; 1.
DR PROSITE; PS50112; PAS; 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; Hydrolase; Metal-binding;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1..829
FT /note="High affinity cAMP-specific and IBMX-insensitive
FT 3',5'-cyclic phosphodiesterase 8A"
FT /id="PRO_0000198838"
FT DOMAIN 213..283
FT /note="PAS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 287..329
FT /note="PAC"
FT DOMAIN 480..820
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 16..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 341..360
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 454..461
FT /note="Involved in RAF1-binding"
FT /evidence="ECO:0000269|PubMed:23509299"
FT COMPBIAS 346..360
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 556
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 560
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18983167,
FT ECO:0000312|PDB:3ECN, ECO:0007744|PDB:3ECM"
FT BINDING 596
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18983167,
FT ECO:0000312|PDB:3ECN, ECO:0007744|PDB:3ECM"
FT BINDING 597
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18983167,
FT ECO:0000312|PDB:3ECN, ECO:0007744|PDB:3ECM"
FT BINDING 597
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:18983167,
FT ECO:0000312|PDB:3ECN, ECO:0007744|PDB:3ECM"
FT BINDING 726
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:18983167,
FT ECO:0000312|PDB:3ECN, ECO:0007744|PDB:3ECM"
FT MOD_RES 20
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18691976,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 359
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:22673573"
FT MOD_RES 386
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88502"
FT MOD_RES 457
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 461
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:O88502"
FT VAR_SEQ 1..72
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046017"
FT VAR_SEQ 212..228
FT /note="RACNSVFTALENSEDAI -> SMQILHLKQQWAISQVN (in isoform
FT 4)"
FT /evidence="ECO:0000303|PubMed:11738832"
FT /id="VSP_041674"
FT VAR_SEQ 213..231
FT /note="ACNSVFTALENSEDAIEIT -> SGKEFTMQKRKTEIIYNKM (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:11738832"
FT /id="VSP_041675"
FT VAR_SEQ 229..829
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:11738832"
FT /id="VSP_041676"
FT VAR_SEQ 232..829
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:11738832"
FT /id="VSP_041677"
FT VAR_SEQ 239..284
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11738832,
FT ECO:0000303|PubMed:9618252"
FT /id="VSP_004597"
FT VAR_SEQ 239..272
FT /note="YANPAFETTMGYQSGELIGKELGEVPINEKKADL -> PCCSSSWFGAAHIP
FT SSAPVEVGVGLLPSWSLRRT (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:11738832"
FT /id="VSP_041678"
FT VAR_SEQ 273..829
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:11738832"
FT /id="VSP_041679"
FT VARIANT 112
FT /note="E -> G (in dbSNP:rs17855018)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_069109"
FT MUTAGEN 454..455
FT /note="RR->AA: Reduces interaction with RAF1; when
FT associated with A-460 and A-461."
FT /evidence="ECO:0000269|PubMed:23509299"
FT MUTAGEN 460..461
FT /note="EY->AA: Reduces interaction with RAF1; when
FT associated with A-454 and A-455."
FT /evidence="ECO:0000269|PubMed:23509299"
FT MUTAGEN 748
FT /note="Y->F: Increases sensitivity to several nonselective
FT or family selective PDE inhibitors."
FT /evidence="ECO:0000269|PubMed:18983167"
FT CONFLICT 55
FT /note="L -> V (in Ref. 2; AAK57641)"
FT /evidence="ECO:0000305"
FT CONFLICT 344
FT /note="H -> R (in Ref. 2; AAK57641 and 7; AAC39763)"
FT /evidence="ECO:0000305"
FT CONFLICT 399
FT /note="I -> V (in Ref. 2; AAK57641 and 7; AAC39763)"
FT /evidence="ECO:0000305"
FT HELIX 486..491
FT /evidence="ECO:0007829|PDB:3ECM"
FT TURN 492..496
FT /evidence="ECO:0007829|PDB:3ECM"
FT STRAND 497..499
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 502..508
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 513..524
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 528..531
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 535..547
FT /evidence="ECO:0007829|PDB:3ECM"
FT STRAND 553..557
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 558..572
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 575..578
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 583..595
FT /evidence="ECO:0007829|PDB:3ECM"
FT TURN 596..599
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 605..610
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 614..618
FT /evidence="ECO:0007829|PDB:3ECM"
FT TURN 619..621
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 624..638
FT /evidence="ECO:0007829|PDB:3ECM"
FT TURN 641..643
FT /evidence="ECO:0007829|PDB:3ECM"
FT TURN 645..648
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 651..666
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 670..672
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 673..683
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 685..691
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 692..694
FT /evidence="ECO:0007829|PDB:3ECN"
FT HELIX 698..708
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 711..726
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 729..731
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 734..758
FT /evidence="ECO:0007829|PDB:3ECM"
FT TURN 769..771
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 774..784
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 786..797
FT /evidence="ECO:0007829|PDB:3ECM"
FT HELIX 800..814
FT /evidence="ECO:0007829|PDB:3ECM"
SQ SEQUENCE 829 AA; 93304 MW; 99BD05EA185A42CD CRC64;
MGCAPSIHIS ERLVAEDAPS PAAPPLSSGG PRLPQGQKTA ALPRTRGAGL LESELRDGSG
KKVAVADVQF GPMRFHQDQL QVLLVFTKED NQCNGFCRAC EKAGFKCTVT KEAQAVLACF
LDKHHDIIII DHRNPRQLDA EALCRSIRSS KLSENTVIVG VVRRVDREEL SVMPFISAGF
TRRYVENPNI MACYNELLQL EFGEVRSQLK LRACNSVFTA LENSEDAIEI TSEDRFIQYA
NPAFETTMGY QSGELIGKEL GEVPINEKKA DLLDTINSCI RIGKEWQGIY YAKKKNGDNI
QQNVKIIPVI GQGGKIRHYV SIIRVCNGNN KAEKISECVQ SDTHTDNQTG KHKDRRKGSL
DVKAVASRAT EVSSQRRHSS MARIHSMTIE APITKVINII NAAQESSPMP VTEALDRVLE
ILRTTELYSP QFGAKDDDPH ANDLVGGLMS DGLRRLSGNE YVLSTKNTQM VSSNIITPIS
LDDVPPRIAR AMENEEYWDF DIFELEAATH NRPLIYLGLK MFARFGICEF LHCSESTLRS
WLQIIEANYH SSNPYHNSTH SADVLHATAY FLSKERIKET LDPIDEVAAL IAATIHDVDH
PGRTNSFLCN AGSELAILYN DTAVLESHHA ALAFQLTTGD DKCNIFKNME RNDYRTLRQG
IIDMVLATEM TKHFEHVNKF VNSINKPLAT LEENGETDKN QEVINTMLRT PENRTLIKRM
LIKCADVSNP CRPLQYCIEW AARISEEYFS QTDEEKQQGL PVVMPVFDRN TCSIPKSQIS
FIDYFITDMF DAWDAFVDLP DLMQHLDNNF KYWKGLDEMK LRNLRPPPE
