PDE8A_MOUSE
ID PDE8A_MOUSE Reviewed; 823 AA.
AC O88502; Q059P6;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A;
DE Short=MmPDE8;
DE EC=3.1.4.53 {ECO:0000269|PubMed:9671792};
GN Name=Pde8a; Synonyms=Pde8;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC TISSUE=Testis;
RX PubMed=9671792; DOI=10.1073/pnas.95.15.8991;
RA Soderling S.H., Bayuga S.J., Beavo J.A.;
RT "Cloning and characterization of a cAMP-specific cyclic nucleotide
RT phosphodiesterase.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:8991-8996(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-456, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-382 AND SER-452, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Lung, Spleen, and
RC Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP DISRUPTION PHENOTYPE.
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).
CC -!- FUNCTION: Hydrolyzes the second messenger cAMP, which is a key
CC regulator of many important physiological processes. May be involved in
CC maintaining basal levels of the cyclic nucleotide and/or in the cAMP
CC regulation of germ cell development. Binding to RAF1 reduces RAF1 'Ser-
CC 259' inhibitory-phosphorylation and stimulates RAF1-dependent EGF-
CC activated ERK-signaling. Protects against cell death induced by
CC hydrogen peroxide and staurosporine. {ECO:0000250|UniProtKB:O60658}.
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:9671792};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25278;
CC Evidence={ECO:0000269|PubMed:9671792};
CC -!- COFACTOR:
CC Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240;
CC Evidence={ECO:0000250};
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:0000250};
CC -!- ACTIVITY REGULATION: Inhibited by dipyridimole. Insensitive to
CC selective PDE inhibitor rolipram and to the non-selective inhibitor,
CC IBMX.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.15 uM for cAMP {ECO:0000269|PubMed:9671792};
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:0000250|UniProtKB:O60658}.
CC -!- TISSUE SPECIFICITY: Expressed in multiple tissues, with highest levels
CC in testis, followed by liver, heart, skeletal muscle, and kidney. In
CC the testis, expressed specifically in the seminiferous tubules, in
CC postmitotic pachytene spermatocytes (PubMed:9671792). Low expression,
CC if any, in lung, smooth muscle, pancreas, thyroid, thymus, submaxillary
CC gland, spleen, prostate, epididymus, uterus (PubMed:9671792).
CC {ECO:0000269|PubMed:9671792}.
CC -!- DEVELOPMENTAL STAGE: Expressed in embryos at 7 dpc. Not detected at
CC later stages, including 11, 15 and 17 dpc (PubMed:9671792). In the
CC testis, expression restricted to middle and late pachytene
CC spermatocytes (PubMed:9671792). {ECO:0000269|PubMed:9671792}.
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-355 by PKA under elevated cAMP conditions,
CC this enhances catalytic activity. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Reduced phosphorylation of Mapk1/Erk2 and
CC Mapk3/Erk1, both basal levels and those induced by EGF treatment.
CC {ECO:0000269|PubMed:23509299}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC PDE8 subfamily. {ECO:0000305}.
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DR EMBL; AF067806; AAC40194.1; -; mRNA.
DR EMBL; BC125578; AAI25579.1; -; mRNA.
DR EMBL; BC132145; AAI32146.1; -; mRNA.
DR CCDS; CCDS40005.1; -.
DR RefSeq; NP_032829.1; NM_008803.2.
DR AlphaFoldDB; O88502; -.
DR SMR; O88502; -.
DR BioGRID; 202082; 12.
DR STRING; 10090.ENSMUSP00000026672; -.
DR iPTMnet; O88502; -.
DR PhosphoSitePlus; O88502; -.
DR jPOST; O88502; -.
DR MaxQB; O88502; -.
DR PaxDb; O88502; -.
DR PeptideAtlas; O88502; -.
DR PRIDE; O88502; -.
DR ProteomicsDB; 294042; -.
DR Antibodypedia; 679; 289 antibodies from 33 providers.
DR DNASU; 18584; -.
DR Ensembl; ENSMUST00000026672; ENSMUSP00000026672; ENSMUSG00000025584.
DR GeneID; 18584; -.
DR KEGG; mmu:18584; -.
DR UCSC; uc009ibt.1; mouse.
DR CTD; 5151; -.
DR MGI; MGI:1277116; Pde8a.
DR VEuPathDB; HostDB:ENSMUSG00000025584; -.
DR eggNOG; KOG1229; Eukaryota.
DR GeneTree; ENSGT00940000156422; -.
DR HOGENOM; CLU_005940_4_2_1; -.
DR InParanoid; O88502; -.
DR OMA; HWDFDIF; -.
DR OrthoDB; 904682at2759; -.
DR PhylomeDB; O88502; -.
DR TreeFam; TF314638; -.
DR BRENDA; 3.1.4.53; 3474.
DR Reactome; R-MMU-418555; G alpha (s) signalling events.
DR UniPathway; UPA00762; UER00747.
DR BioGRID-ORCS; 18584; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Pde8a; mouse.
DR PRO; PR:O88502; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; O88502; protein.
DR Bgee; ENSMUSG00000025584; Expressed in seminiferous tubule of testis and 226 other tissues.
DR Genevisible; O88502; MM.
DR GO; GO:0004115; F:3',5'-cyclic-AMP phosphodiesterase activity; IDA:MGI.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; ISO:MGI.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
DR GO; GO:0019900; F:kinase binding; ISO:MGI.
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; ISO:MGI.
DR GO; GO:1903206; P:negative regulation of hydrogen peroxide-induced cell death; ISO:MGI.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISO:MGI.
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 cAMP; Hydrolase; Metal-binding; Phosphoprotein; Reference proteome.
FT CHAIN 1..823
FT /note="High affinity cAMP-specific and IBMX-insensitive
FT 3',5'-cyclic phosphodiesterase 8A"
FT /id="PRO_0000198839"
FT DOMAIN 209..280
FT /note="PAS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140"
FT DOMAIN 283..325
FT /note="PAC"
FT DOMAIN 475..814
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 1..55
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 338..373
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 343..360
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 551
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 555
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O60658"
FT BINDING 591
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O60658"
FT BINDING 592
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O60658"
FT BINDING 592
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:O60658"
FT BINDING 720
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:O60658"
FT MOD_RES 355
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000250|UniProtKB:O60658"
FT MOD_RES 382
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 452
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 456
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:19144319"
SQ SEQUENCE 823 AA; 93171 MW; 7FD9BE4BAEB9BCF2 CRC64;
MGCAPSIHTS ENRTFSHSDG EDEDVDVDVP GPAPRSIQRW STAPGLVEPQ PRDNGASKVS
VADVQFGPMR FHQDQLQVLL VFTKEDSQCN GFHRACEKAG FKCTVTKEVQ TVLTCFQDKL
HDIIIIDHRY PRQMDAETLC RSIRSSKFSE NTVIVGVVRR VDKEESSLMP FLAAGFTRRF
IENPNVMACY NELLQLACGE VRSQLKLRAC NSVFTALEKS QEAIEITSED HIIQYANPAF
ESTMGYQSGE LIGKELAQVP INEKKGDLLD AINSCVTVDK EWQGVYHTQK KNGDNIQQNV
KIIPVIGQGG KIRHYVSIIR VCNGNNKVET TTECVQTDSQ TDNQAGKHKD RRKHSMDAKA
VSSRTSDVSS QRRHSSLARI HSMMIEAPIT KVINIINAAQ ENSPVPVTEA LNRVLDILRT
TELYSPQFNA QDDPHATDLV GGLMSDGLRR FSGNEYILAT KNLPPLSNNL ATPVSLHDVP
PRIALAIENE EQWDFDIFEL EVATQNRPLI YLGLKTFARF GMCEFLQCSE TTLRSWFQMI
ESNYHSSNPY HNSTHAADVL HATAYFLSRD KIKETLDRID EVAALIAATV HDVDHPGRTN
SFLCNAGNQL AVLYNDTAVL ESHHVALAFQ LTLENDQCNI FKQMERNDYR TLRQSIIDMV
LATEMTKHFE HVNKFINSIN KPLTAQESEE PDRSLEDIKA MLKTPESRAL IKRMMIKCAD
VSNPCRPLEH CIEWAARISE EYFSQTDEEK QLDLPVVMPV FDRNTCSIPK SQISFIDYFI
TDMFDAWDAF VDLPNLMQHL DDNFRYWKGL DEKKLRSLRP PPE
