PDE6_DROME
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 03-AUG-2022, entry version 148.
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.FBpp0289559; -.
DR PaxDb; Q9VFI9; -.
DR PRIDE; Q9VFI9; -.
DR EnsemblMetazoa; FBtr0300330; FBpp0289559; FBgn0038237.
DR EnsemblMetazoa; FBtr0345168; FBpp0311378; FBgn0038237.
DR GeneID; 41760; -.
DR KEGG; dme:Dmel_CG8279; -.
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 OrthoDB; 904682at2759; -.
DR Reactome; R-DME-2485179; Activation of the phototransduction cascade.
DR Reactome; R-DME-4086398; Ca2+ pathway.
DR Reactome; R-DME-418457; cGMP effects.
DR Reactome; R-DME-418555; G alpha (s) signalling events.
DR Reactome; R-DME-9013422; RHOBTB1 GTPase cycle.
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 tissues.
DR ExpressionAtlas; Q9VFI9; baseline and differential.
DR Genevisible; Q9VFI9; DM.
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; 1.10.1300.10; -; 1.
DR Gene3D; 3.30.450.40; -; 2.
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 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 PROSITE; PS00126; PDEASE_I_1; 1.
DR PROSITE; PS51845; PDEASE_I_2; 1.
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
