ID   PDE6_DROME              Reviewed;        1118 AA.
AC   Q9VFI9; Q95TW8;
DT   16-DEC-2008, integrated into UniProtKB/Swiss-Prot.
DT   19-OCT-2011, sequence version 4.
DT   24-JAN-2024, entry version 155.
DE   RecName: Full=cGMP-specific 3',5'-cyclic phosphodiesterase {ECO:0000303|PubMed:16232123};
DE            EC=3.1.4.35 {ECO:0000269|PubMed:15673286, ECO:0000269|PubMed:16232123, ECO:0000269|PubMed:18503409};
DE   AltName: Full=DmPDE5/6;
DE            Short=DmPDE6 {ECO:0000303|PubMed:16232123};
DE   Flags: Precursor;
GN   Name=Pde6; ORFNames=CG8279;
OS   Drosophila melanogaster (Fruit fly).
OC   Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC   Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC   Drosophilidae; Drosophila; Sophophora.
OX   NCBI_TaxID=7227;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Berkeley;
RX   PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA   Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA   Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA   George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA   Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA   Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA   Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA   An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA   Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA   Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA   Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA   Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA   Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA   Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA   Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA   Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA   Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA   Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA   Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA   Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA   Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA   Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA   McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA   Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA   Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA   Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA   Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA   Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA   Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA   Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA   Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA   Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA   Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA   Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA   Venter J.C.;
RT   "The genome sequence of Drosophila melanogaster.";
RL   Science 287:2185-2195(2000).
RN   [2] {ECO:0000305}
RP   GENOME REANNOTATION.
RC   STRAIN=Berkeley;
RX   PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA   Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA   Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA   Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA   Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA   Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA   Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT   "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT   review.";
RL   Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN   [3] {ECO:0000305, ECO:0000312|EMBL:AAL13699.1}
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 84-1118.
RC   STRAIN=Berkeley {ECO:0000312|EMBL:AAL13699.1};
RC   TISSUE=Head {ECO:0000269|PubMed:12537569};
RX   PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA   Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA   Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA   Celniker S.E.;
RT   "A Drosophila full-length cDNA resource.";
RL   Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
RN   [4]
RP   FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP   PROPERTIES, AND TISSUE SPECIFICITY.
RX   PubMed=15673286; DOI=10.1042/bj20050057;
RA   Day J.P., Dow J.A.T., Houslay M.D., Davies S.A.;
RT   "Cyclic nucleotide phosphodiesterases in Drosophila melanogaster.";
RL   Biochem. J. 388:333-342(2005).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE,
RP   AND TISSUE SPECIFICITY.
RX   PubMed=16232123; DOI=10.1042/bj20051505;
RA   Day J.P., Houslay M.D., Davies S.-A.;
RT   "A novel role for a Drosophila homologue of cGMP-specific phosphodiesterase
RT   in the active transport of cGMP.";
RL   Biochem. J. 393:481-488(2006).
RN   [6]
RP   CATALYTIC ACTIVITY, INTERACTION WITH PRBP, SUBCELLULAR LOCATION,
RP   ISOPRENYLATION AT CYS-1115, AND MUTAGENESIS OF CYS-1115.
RX   PubMed=18503409; DOI=10.1042/bj20080560;
RA   Day J.P., Cleghon V., Houslay M.D., Davies S.-A.;
RT   "Regulation of a Drosophila melanogaster cGMP-specific phosphodiesterase by
RT   prenylation and interaction with a prenyl-binding protein.";
RL   Biochem. J. 414:363-374(2008).
CC   -!- FUNCTION: Hydrolyzes the second messenger cGMP, which is a key
CC       regulator of many important physiological processes (PubMed:15673286).
CC       Has cAMP phosphodiesterase activity in vitro but not in vivo
CC       (PubMed:15673286). Has a role regulating cGMP transport in Malpighian
CC       tubule principal cells (PubMed:16232123). {ECO:0000269|PubMed:15673286,
CC       ECO:0000269|PubMed:16232123}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=3',5'-cyclic GMP + H2O = GMP + H(+); Xref=Rhea:RHEA:16957,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57746,
CC         ChEBI:CHEBI:58115; EC=3.1.4.35;
CC         Evidence={ECO:0000269|PubMed:15673286, ECO:0000269|PubMed:16232123,
CC         ECO:0000269|PubMed:18503409};
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 sildenafil and zaprinast.
CC       {ECO:0000269|PubMed:15673286}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=37 uM for cGMP {ECO:0000269|PubMed:15673286};
CC   -!- SUBUNIT: Interacts with PrBP. {ECO:0000269|PubMed:18503409}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16232123,
CC       ECO:0000269|PubMed:18503409}; Lipid-anchor
CC       {ECO:0000269|PubMed:16232123, ECO:0000269|PubMed:18503409}; Cytoplasmic
CC       side {ECO:0000269|PubMed:16232123, ECO:0000269|PubMed:18503409}.
CC       Note=Expressed on the apical side of the Malpighian tubule principal
CC       cell polarized membrane. Loss of prenylation causes protein location to
CC       the cytoplasm.
CC   -!- TISSUE SPECIFICITY: Expressed in Malpighian tubule principal cells
CC       (PubMed:16232123, PubMed:15673286). Also expressed in adult head
CC       (PubMed:15673286). {ECO:0000269|PubMed:15673286,
CC       ECO:0000269|PubMed:16232123}.
CC   -!- DISRUPTION PHENOTYPE: Flies display increased active transport of cGMP.
CC       Overexpression of Pde6 confers inhibition of the active transport and
CC       efflux of cGMP by tubules. {ECO:0000269|PubMed:16232123}.
CC   -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC       {ECO:0000255}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAL13699.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; AE014297; AAF55066.4; -; Genomic_DNA.
DR   EMBL; AY058470; AAL13699.1; ALT_INIT; mRNA.
DR   RefSeq; NP_001287327.1; NM_001300398.1.
DR   RefSeq; NP_650369.3; NM_142112.5.
DR   AlphaFoldDB; Q9VFI9; -.
DR   SMR; Q9VFI9; -.
DR   BioGRID; 66835; 1.
DR   STRING; 7227.FBpp0303081; -.
DR   PaxDb; 7227-FBpp0289559; -.
DR   EnsemblMetazoa; FBtr0300330; FBpp0289559; FBgn0038237.
DR   EnsemblMetazoa; FBtr0345168; FBpp0311378; FBgn0038237.
DR   GeneID; 41760; -.
DR   KEGG; dme:Dmel_CG8279; -.
DR   AGR; FB:FBgn0038237; -.
DR   CTD; 41760; -.
DR   FlyBase; FBgn0038237; Pde6.
DR   VEuPathDB; VectorBase:FBgn0038237; -.
DR   eggNOG; KOG3689; Eukaryota.
DR   HOGENOM; CLU_006980_0_2_1; -.
DR   InParanoid; Q9VFI9; -.
DR   OMA; ATIRMFK; -.
DR   BioGRID-ORCS; 41760; 0 hits in 3 CRISPR screens.
DR   ChiTaRS; Pde6; fly.
DR   GenomeRNAi; 41760; -.
DR   PRO; PR:Q9VFI9; -.
DR   Proteomes; UP000000803; Chromosome 3R.
DR   Bgee; FBgn0038237; Expressed in spermathecum and 16 other cell types or tissues.
DR   ExpressionAtlas; Q9VFI9; baseline and differential.
DR   GO; GO:0016324; C:apical plasma membrane; IDA:FlyBase.
DR   GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; IDA:FlyBase.
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:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0046068; P:cGMP metabolic process; IDA:UniProtKB.
DR   GO; GO:0032240; P:negative regulation of nucleobase-containing compound transport; IMP:FlyBase.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR   CDD; cd00077; HDc; 1.
DR   Gene3D; 3.30.450.40; -; 2.
DR   Gene3D; 1.10.1300.10; 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain; 1.
DR   InterPro; IPR003018; GAF.
DR   InterPro; IPR029016; GAF-like_dom_sf.
DR   InterPro; IPR003607; HD/PDEase_dom.
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; CYCLIC NUCLEOTIDE PHOSPHODIESTERASE; 1.
DR   PANTHER; PTHR11347:SF216; PHOSPHODIESTERASE; 1.
DR   Pfam; PF01590; GAF; 2.
DR   Pfam; PF00233; PDEase_I; 1.
DR   PRINTS; PR00387; PDIESTERASE1.
DR   SMART; SM00065; GAF; 2.
DR   SMART; SM00471; HDc; 1.
DR   SUPFAM; SSF55781; GAF domain-like; 2.
DR   SUPFAM; SSF109604; HD-domain/PDEase-like; 1.
DR   PROSITE; PS00126; PDEASE_I_1; 1.
DR   PROSITE; PS51845; PDEASE_I_2; 1.
DR   Genevisible; Q9VFI9; DM.
PE   1: Evidence at protein level;
KW   Cell membrane; cGMP; Hydrolase; Lipoprotein; Membrane; Metal-binding;
KW   Methylation; Prenylation; Reference proteome; Repeat.
FT   CHAIN           1..1115
FT                   /note="cGMP-specific 3',5'-cyclic phosphodiesterase"
FT                   /id="PRO_0000356892"
FT   PROPEP          1116..1118
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000305"
FT                   /id="PRO_0000356893"
FT   DOMAIN          247..399
FT                   /note="GAF 1"
FT   DOMAIN          431..612
FT                   /note="GAF 2"
FT   DOMAIN          642..965
FT                   /note="PDEase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT   REGION          1..142
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1006..1035
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1065..1118
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1..48
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        86..142
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1074..1105
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        718
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250"
FT   BINDING         722
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         758
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         759
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         759
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         869
FT                   /ligand="a divalent metal cation"
FT                   /ligand_id="ChEBI:CHEBI:60240"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         1115
FT                   /note="Cysteine methyl ester"
FT                   /evidence="ECO:0000305"
FT   LIPID           1115
FT                   /note="S-farnesyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:18503409"
FT   MUTAGEN         1115
FT                   /note="C->S: Impairs prenylation and membrane."
FT                   /evidence="ECO:0000269|PubMed:18503409"
SQ   SEQUENCE   1118 AA;  124325 MW;  1CFB89721F84DC5A CRC64;
     MTDVSSPAGG AASPVEMSTT SSSSAATTSA SSSKPLTNGA NKTAISTAAG GVTPGAVPGP
     GSGAIPASSS SGNQVKLEHH HRQSNNNRPA VTNRSSETKL MTPTGSSSSP SQSPSQTQAS
     IQTQTSQQDR LAKASTTASQ QDVDEVARLF EEKPEAFEKW LTERAPPEAL SRLQEFIENR
     KPHKRPSVTS DLFQQWMAAS PTVQQKSPRS LSNSSASSLP ECRRHLMDLD EGELFMELIR
     DVANELDIDV LCHKILVNVG LLTHADRGSL FLAKGTPTNK YLVAKLFDVT QKTALKDAVT
     RASAEEIIIP FGIGIAGMVA QTKQMINIKE AYKDARFNCE IDLKTGYKTN AILCMPICNY
     EGDIIGVAQI INKTNGCMEF DEHDVEIFRR YLTFCGIGIQ NAQLFEMSVQ EYRRNQILLN
     LARSIFEEQN NLECLVTKIM TEARELLKCE RCSVFLVDLD CCEASHLEKI IEKPNQPATR
     AIKSADSFEE KKMRNRFTVL FELGGEYQAA NVSRPSVSEL SSSTLAQIAQ FVATTGQTVN
     ICDVIEWVRD HNQIRAEDEI DSTQAILCMP IMNAQKKVIG VAQLINKANG VPFTDSDASI
     FEAFAIFCGL GIHNTQMYEN ACKLMAKQKV ALECLSYHAT ASQDQTEKLT QDVIAEAESY
     NLYSFTFTDF ELVDDDTCRA VLRMFMQCNL VSQFQIPYDV LCRWVLSVRK NYRPVKYHNW
     RHALNVAQTM FAMLKTGKME RFMTDLEILG LLVACLCHDL DHRGTNNAFQ TKTESPLAIL
     YTTSTMEHHH FDQCVMILNS EGNNIFQALS PEDYRSVMKT VESAILSTDL AMYFKKRNAF
     LELVENGEFD WQGEEKKDLL CGMMMTACDV SAIAKPWEVQ HKVAKLVADE FFDQGDLEKL
     QLNTQPVAMM DRERKDELPK MQVGFIDVIC LPLYRVLCDT FPWITPLYEG TLENRRNWQD
     LAEKVEMGLT WIDHDTIDKP VEEFAACADE EIKDIEFTVT TLNCNQQSQH GSEDSHTPEH
     QRSGSRLSMK KTGALGKAVR SKLSKTLYNS MDGSKPKTSL KLLESHVSED MDDKSPTSPS
     QPQASGSMGR MSASSSTSSA GGQMVDKSKK RSKLCALL
//