PDE6A_HUMAN
ID PDE6A_HUMAN Reviewed; 860 AA.
AC P16499; Q0P638;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2008, sequence version 4.
DT 03-AUG-2022, entry version 201.
DE RecName: Full=Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha {ECO:0000305};
DE Short=GMP-PDE alpha;
DE EC=3.1.4.35 {ECO:0000269|PubMed:20940301};
DE AltName: Full=PDE V-B1;
DE Flags: Precursor;
GN Name=PDE6A {ECO:0000312|HGNC:HGNC:8785}; Synonyms=PDEA;
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].
RX PubMed=2155175; DOI=10.1016/0888-7543(90)90567-e;
RA Pittler S.J., Baehr W., Wasmuth J.J., McConnell D.G., Champagne M.S.,
RA VanTuinen P., Ledbetter D., Davis R.L.;
RT "Molecular characterization of human and bovine rod photoreceptor cGMP
RT phosphodiesterase alpha-subunit and chromosomal localization of the human
RT gene.";
RL Genomics 6:272-283(1990).
RN [2]
RP SEQUENCE REVISION TO 846-849.
RA Pittler S.J., Baehr W., Wasmuth J.J., McConnell D.G., Champagne M.S.,
RA Vantuinen P., Ledbetter D., Davis R.L.;
RL Submitted (MAY-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
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 [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP SUBCELLULAR LOCATION.
RX PubMed=20940301; DOI=10.1074/jbc.m110.170068;
RA Muradov H., Boyd K.K., Artemyev N.O.;
RT "Rod phosphodiesterase-6 PDE6A and PDE6B subunits are enzymatically
RT equivalent.";
RL J. Biol. Chem. 285:39828-39834(2010).
RN [6]
RP VARIANT RP43 ARG-344.
RX PubMed=7493036; DOI=10.1038/ng1295-468;
RA Huang S.H., Pittler S.J., Huang X., Oliveira L., Berson E.L., Dryja T.P.;
RT "Autosomal recessive retinitis pigmentosa caused by mutations in the alpha
RT subunit of rod cGMP phosphodiesterase.";
RL Nat. Genet. 11:468-471(1995).
RN [7]
RP VARIANTS RP43 HIS-102; SER-102; LYS-569 AND PRO-573, AND VARIANTS SER-216;
RP ALA-277; LEU-293; MET-391; GLN-827 AND VAL-850.
RX PubMed=10393062;
RA Dryja T.P., Rucinski D.E., Chen S.H., Berson E.L.;
RT "Frequency of mutations in the gene encoding the alpha subunit of rod cGMP-
RT phosphodiesterase in autosomal recessive retinitis pigmentosa.";
RL Invest. Ophthalmol. Vis. Sci. 40:1859-1865(1999).
CC -!- FUNCTION: Rod-specific cGMP phosphodiesterase that catalyzes the
CC hydrolysis of 3',5'-cyclic GMP (PubMed:20940301). This protein
CC participates in processes of transmission and amplification of the
CC visual signal. {ECO:0000269|PubMed:20940301}.
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:20940301};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958;
CC Evidence={ECO:0000305|PubMed:20940301};
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 -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=20 uM for 3',5'-cyclic GMP (with the chimera containing the N-
CC terminal regulatory GAF domains of PDE6C and the C-terminal catalytic
CC domain of PDE6A) {ECO:0000269|PubMed:20940301};
CC -!- SUBUNIT: Oligomer composed of two catalytic chains (alpha and beta), an
CC inhibitory chain (gamma) and the delta chain.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Lipid-anchor
CC {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Cell projection, cilium,
CC photoreceptor outer segment {ECO:0000269|PubMed:20940301}.
CC -!- DISEASE: Retinitis pigmentosa 43 (RP43) [MIM:613810]: A retinal
CC dystrophy belonging to the group of pigmentary retinopathies. Retinitis
CC pigmentosa is characterized by retinal pigment deposits visible on
CC fundus examination and primary loss of rod photoreceptor cells followed
CC by secondary loss of cone photoreceptors. Patients typically have night
CC vision blindness and loss of midperipheral visual field. As their
CC condition progresses, they lose their far peripheral visual field and
CC eventually central vision as well. {ECO:0000269|PubMed:10393062,
CC ECO:0000269|PubMed:7493036}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Mutations of the PDE6A/B/G genes; Note=Retina
CC International's Scientific Newsletter;
CC URL="https://www.retina-international.org/files/sci-news/pdemut.htm";
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DR EMBL; M26061; AAB69155.1; -; mRNA.
DR EMBL; CH471062; EAW61757.1; -; Genomic_DNA.
DR EMBL; BC035909; AAH35909.1; -; mRNA.
DR CCDS; CCDS4299.1; -.
DR PIR; B34611; B34611.
DR RefSeq; NP_000431.2; NM_000440.2.
DR AlphaFoldDB; P16499; -.
DR SMR; P16499; -.
DR BioGRID; 111171; 8.
DR IntAct; P16499; 3.
DR STRING; 9606.ENSP00000255266; -.
DR BindingDB; P16499; -.
DR ChEMBL; CHEMBL3878; -.
DR DrugBank; DB00201; Caffeine.
DR DrugBank; DB09283; Trapidil.
DR DrugCentral; P16499; -.
DR GuidetoPHARMACOLOGY; 1312; -.
DR iPTMnet; P16499; -.
DR PhosphoSitePlus; P16499; -.
DR BioMuta; PDE6A; -.
DR DMDM; 215274230; -.
DR MassIVE; P16499; -.
DR PaxDb; P16499; -.
DR PeptideAtlas; P16499; -.
DR PRIDE; P16499; -.
DR ProteomicsDB; 53376; -.
DR Antibodypedia; 16063; 169 antibodies from 30 providers.
DR DNASU; 5145; -.
DR Ensembl; ENST00000255266.10; ENSP00000255266.5; ENSG00000132915.12.
DR GeneID; 5145; -.
DR KEGG; hsa:5145; -.
DR MANE-Select; ENST00000255266.10; ENSP00000255266.5; NM_000440.3; NP_000431.2.
DR UCSC; uc003lrg.4; human.
DR CTD; 5145; -.
DR DisGeNET; 5145; -.
DR GeneCards; PDE6A; -.
DR GeneReviews; PDE6A; -.
DR HGNC; HGNC:8785; PDE6A.
DR HPA; ENSG00000132915; Tissue enriched (retina).
DR MalaCards; PDE6A; -.
DR MIM; 180071; gene.
DR MIM; 613810; phenotype.
DR neXtProt; NX_P16499; -.
DR OpenTargets; ENSG00000132915; -.
DR Orphanet; 791; Retinitis pigmentosa.
DR PharmGKB; PA33133; -.
DR VEuPathDB; HostDB:ENSG00000132915; -.
DR eggNOG; KOG3689; Eukaryota.
DR GeneTree; ENSGT00940000161330; -.
DR OMA; GPHFTKR; -.
DR OrthoDB; 1274244at2759; -.
DR PhylomeDB; P16499; -.
DR TreeFam; TF316499; -.
DR PathwayCommons; P16499; -.
DR Reactome; R-HSA-2485179; Activation of the phototransduction cascade.
DR Reactome; R-HSA-2514859; Inactivation, recovery and regulation of the phototransduction cascade.
DR Reactome; R-HSA-4086398; Ca2+ pathway.
DR SignaLink; P16499; -.
DR SIGNOR; P16499; -.
DR BioGRID-ORCS; 5145; 10 hits in 1069 CRISPR screens.
DR ChiTaRS; PDE6A; human.
DR GeneWiki; PDE6A; -.
DR GenomeRNAi; 5145; -.
DR Pharos; P16499; Tclin.
DR PRO; PR:P16499; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P16499; protein.
DR Bgee; ENSG00000132915; Expressed in corpus epididymis and 57 other tissues.
DR ExpressionAtlas; P16499; baseline and differential.
DR Genevisible; P16499; HS.
DR GO; GO:0097381; C:photoreceptor disc membrane; TAS:Reactome.
DR GO; GO:0042622; C:photoreceptor outer segment membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; IEA:UniProtKB-EC.
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:0060041; P:retina development in camera-type eye; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0007601; P:visual perception; TAS:ProtInc.
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; IPR032958; PDE6A.
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:SF115; PTHR11347:SF115; 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 PROSITE; PS00126; PDEASE_I_1; 1.
DR PROSITE; PS51845; PDEASE_I_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cell membrane; Cell projection; cGMP; Disease variant;
KW Hydrolase; Lipoprotein; Membrane; Metal-binding; Methylation; Prenylation;
KW Reference proteome; Repeat; Retinitis pigmentosa; Sensory transduction;
KW Vision.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P11541"
FT CHAIN 2..857
FT /note="Rod cGMP-specific 3',5'-cyclic phosphodiesterase
FT subunit alpha"
FT /id="PRO_0000198828"
FT PROPEP 858..860
FT /note="Removed in mature form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000396697"
FT DOMAIN 73..222
FT /note="GAF 1"
FT DOMAIN 254..431
FT /note="GAF 2"
FT DOMAIN 483..816
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT REGION 821..860
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 832..860
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 559
FT /note="Proton donor"
FT /evidence="ECO:0000250"
FT BINDING 563
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 599
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 600
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 600
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 720
FT /ligand="a divalent metal cation"
FT /ligand_id="ChEBI:CHEBI:60240"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylglycine"
FT /evidence="ECO:0000250|UniProtKB:P11541"
FT MOD_RES 857
FT /note="Cysteine methyl ester"
FT /evidence="ECO:0000250"
FT LIPID 857
FT /note="S-farnesyl cysteine"
FT /evidence="ECO:0000250"
FT VARIANT 102
FT /note="R -> H (in RP43; dbSNP:rs750539462)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025460"
FT VARIANT 102
FT /note="R -> S (in RP43; dbSNP:rs141252097)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025461"
FT VARIANT 145
FT /note="A -> T (in dbSNP:rs35431421)"
FT /id="VAR_047730"
FT VARIANT 216
FT /note="N -> S (in dbSNP:rs10057110)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025462"
FT VARIANT 277
FT /note="V -> A (in dbSNP:rs145608358)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025463"
FT VARIANT 293
FT /note="P -> L (in dbSNP:rs114973968)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025464"
FT VARIANT 344
FT /note="S -> R (in RP43; dbSNP:rs121918577)"
FT /evidence="ECO:0000269|PubMed:7493036"
FT /id="VAR_006049"
FT VARIANT 391
FT /note="V -> M (in dbSNP:rs61732059)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025465"
FT VARIANT 492
FT /note="Q -> H (in dbSNP:rs17711594)"
FT /id="VAR_047731"
FT VARIANT 569
FT /note="Q -> K (in RP43; dbSNP:rs139444207)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025466"
FT VARIANT 573
FT /note="S -> P (in RP43; dbSNP:rs755527251)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025467"
FT VARIANT 827
FT /note="K -> Q (in dbSNP:rs780450680)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025468"
FT VARIANT 850
FT /note="G -> V (in dbSNP:rs138315990)"
FT /evidence="ECO:0000269|PubMed:10393062"
FT /id="VAR_025469"
FT CONFLICT 224
FT /note="V -> W (in Ref. 1; AAB69155)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 860 AA; 99547 MW; 7EEA48A234C1FE59 CRC64;
MGEVTAEEVE KFLDSNIGFA KQYYNLHYRA KLISDLLGAK EAAVDFSNYH SPSSMEESEI
IFDLLRDFQE NLQTEKCIFN VMKKLCFLLQ ADRMSLFMYR TRNGIAELAT RLFNVHKDAV
LEDCLVMPDQ EIVFPLDMGI VGHVAHSKKI ANVPNTEEDE HFCDFVDILT EYKTKNILAS
PIMNGKDVVA IIMAVNKVDG SHFTKRDEEI LLKYLNFANL IMKVYHLSYL HNCETRRGQI
LLWSGSKVFE ELTDIERQFH KALYTVRAFL NCDRYSVGLL DMTKQKEFFD VWPVLMGEVP
PYSGPRTPDG REINFYKVID YILHGKEDIK VIPNPPPDHW ALVSGLPAYV AQNGLICNIM
NAPAEDFFAF QKEPLDESGW MIKNVLSMPI VNKKEEIVGV ATFYNRKDGK PFDEMDETLM
ESLTQFLGWS VLNPDTYESM NKLENRKDIF QDIVKYHVKC DNEEIQKILK TREVYGKEPW
ECEEEELAEI LQAELPDADK YEINKFHFSD LPLTELELVK CGIQMYYELK VVDKFHIPQE
ALVRFMYSLS KGYRKITYHN WRHGFNVGQT MFSLLVTGKL KRYFTDLEAL AMVTAAFCHD
IDHRGTNNLY QMKSQNPLAK LHGSSILERH HLEFGKTLLR DESLNIFQNL NRRQHEHAIH
MMDIAIIATD LALYFKKRTM FQKIVDQSKT YESEQEWTQY MMLEQTRKEI VMAMMMTACD
LSAITKPWEV QSQVALLVAA EFWEQGDLER TVLQQNPIPM MDRNKADELP KLQVGFIDFV
CTFVYKEFSR FHEEITPMLD GITNNRKEWK ALADEYDAKM KVQEEKKQKQ QSAKSAAAGN
QPGGNPSPGG ATTSKSCCIQ
