PDE5A_BOVIN
ID PDE5A_BOVIN Reviewed; 865 AA.
AC Q28156;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=cGMP-specific 3',5'-cyclic phosphodiesterase;
DE EC=3.1.4.35 {ECO:0000250|UniProtKB:O76074};
DE AltName: Full=cGMP-binding cGMP-specific phosphodiesterase;
DE Short=CGB-PDE;
GN Name=PDE5A; Synonyms=PDE5;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 4-16; 39-55; 90-101;
RP 127-138; 390-409 AND 531-539.
RC TISSUE=Lung;
RX PubMed=8226796; DOI=10.1016/s0021-9258(18)41607-9;
RA McAllister-Lucas L.M., Sonnenburg W.K., Kadlecek A., Seger D., Trong H.L.,
RA Colbran J.L., Thomas M.K., Walsh K.A., Francis S.H., Corbin J.D.,
RA Beavo J.A.;
RT "The structure of a bovine lung cGMP-binding, cGMP-specific
RT phosphodiesterase deduced from a cDNA clone.";
RL J. Biol. Chem. 268:22863-22873(1993).
RN [2]
RP METAL-BINDING.
RX PubMed=8077192; DOI=10.1016/s0021-9258(17)31669-1;
RA Francis S.H., Colbran J.L., McAllister-Lucas L.M., Corbin J.D.;
RT "Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific
RT phosphodiesterase suggest that it is a zinc hydrolase.";
RL J. Biol. Chem. 269:22477-22480(1994).
RN [3]
RP FUNCTION, AND MUTAGENESIS OF ASP-289 AND ASP-478.
RX PubMed=8530505; DOI=10.1074/jbc.270.51.30671;
RA McAllister-Lucas L.M., Haik T.L., Colbran J.L., Sonnenburg W.K., Seger D.,
RA Turko I.V., Beavo J.A., Francis S.H., Corbin J.D.;
RT "An essential aspartic acid at each of two allosteric cGMP-binding sites of
RT a cGMP-specific phosphodiesterase.";
RL J. Biol. Chem. 270:30671-30679(1995).
RN [4]
RP MUTAGENESIS OF ASN-276; LYS-277; ASP-289 AND GLU-290.
RX PubMed=8703039; DOI=10.1074/jbc.271.36.22240;
RA Turko I.V., Haik T.L., McAllister-Lucas L.M., Burns F., Francis S.H.,
RA Corbin J.D.;
RT "Identification of key amino acids in a conserved cGMP-binding site of
RT cGMP-binding phosphodiesterases. A putative NKXnD motif for cGMP binding.";
RL J. Biol. Chem. 271:22240-22244(1996).
RN [5]
RP PHOSPHORYLATION, AND MUTAGENESIS OF ASP-289 AND ASP-478.
RX PubMed=9445376; DOI=10.1042/bj3290505;
RA Turko I.V., Francis S.H., Corbin J.D.;
RT "Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific
RT phosphodiesterase (PDE5) is required for its phosphorylation.";
RL Biochem. J. 329:505-510(1998).
CC -!- FUNCTION: Plays a role in signal transduction by regulating the
CC intracellular concentration of cyclic nucleotides. This
CC phosphodiesterase catalyzes the specific hydrolysis of cGMP to 5'-GMP
CC (PubMed:8530505). Specifically regulates nitric-oxide-generated cGMP
CC (By similarity). {ECO:0000250|UniProtKB:O76074,
CC ECO:0000269|PubMed:8530505}.
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:0000250|UniProtKB:O76074};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16958;
CC Evidence={ECO:0000250|UniProtKB:O76074};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:O76074};
CC Note=Binds 1 Zn(2+) ion per subunit. Binds 2 divalent metal cations per
CC subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Tightly binds zinc.
CC {ECO:0000250|UniProtKB:O76074};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:O76074};
CC Note=Binds 1 Mg(2+) ions per subunit. Binds 2 divalent metal cations
CC per subunit: site 1 preferentially binds zinc, while site 2 has a
CC preference for magnesium. Binds magnesium less tightly than zinc.
CC {ECO:0000250|UniProtKB:O76074};
CC -!- ACTIVITY REGULATION: Most potently inhibited by zaprinast and
CC dipyridamole.
CC -!- PATHWAY: Purine metabolism; 3',5'-cyclic GMP degradation; GMP from
CC 3',5'-cyclic GMP: step 1/1.
CC -!- DOMAIN: Composed of a C-terminal catalytic domain containing two
CC putative divalent metal sites and an N-terminal regulatory domain which
CC contains two homologous allosteric cGMP-binding regions, A and B.
CC -!- PTM: Phosphorylation is regulated by binding of cGMP to the two
CC allosteric sites. Phosphorylation by PRKG1 leads to its activation (By
CC similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the cyclic nucleotide phosphodiesterase family.
CC {ECO:0000305}.
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DR EMBL; L16545; AAB00990.1; -; mRNA.
DR RefSeq; NP_776842.1; NM_174417.2.
DR PDB; 3JAB; EM; 11.00 A; C/O=525-850.
DR PDB; 3JBQ; EM; 11.00 A; B/F=525-850.
DR PDBsum; 3JAB; -.
DR PDBsum; 3JBQ; -.
DR AlphaFoldDB; Q28156; -.
DR SMR; Q28156; -.
DR BioGRID; 159263; 1.
DR STRING; 9913.ENSBTAP00000014479; -.
DR BindingDB; Q28156; -.
DR ChEMBL; CHEMBL3478; -.
DR DrugCentral; Q28156; -.
DR iPTMnet; Q28156; -.
DR PaxDb; Q28156; -.
DR PRIDE; Q28156; -.
DR Ensembl; ENSBTAT00000014479; ENSBTAP00000014479; ENSBTAG00000024888.
DR GeneID; 281972; -.
DR KEGG; bta:281972; -.
DR CTD; 8654; -.
DR VEuPathDB; HostDB:ENSBTAG00000024888; -.
DR VGNC; VGNC:32678; PDE5A.
DR eggNOG; KOG3689; Eukaryota.
DR GeneTree; ENSGT00940000155475; -.
DR HOGENOM; CLU_006980_0_2_1; -.
DR InParanoid; Q28156; -.
DR OrthoDB; 904682at2759; -.
DR TreeFam; TF316499; -.
DR UniPathway; UPA00763; UER00748.
DR PRO; PR:Q28156; -.
DR Proteomes; UP000009136; Chromosome 6.
DR Bgee; ENSBTAG00000024888; Expressed in spiral colon and 109 other tissues.
DR ExpressionAtlas; Q28156; baseline and differential.
DR GO; GO:0047555; F:3',5'-cyclic-GMP phosphodiesterase activity; ISS:AgBase.
DR GO; GO:0004114; F:3',5'-cyclic-nucleotide phosphodiesterase activity; IBA:GO_Central.
DR GO; GO:0030553; F:cGMP binding; ISS:AgBase.
DR GO; GO:0004112; F:cyclic-nucleotide phosphodiesterase activity; ISS:AgBase.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0046069; P:cGMP catabolic process; ISS:AgBase.
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 3D-structure; Allosteric enzyme; cGMP; cGMP-binding;
KW Direct protein sequencing; Hydrolase; Magnesium; Metal-binding;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Repeat; Zinc.
FT CHAIN 1..865
FT /note="cGMP-specific 3',5'-cyclic phosphodiesterase"
FT /id="PRO_0000198821"
FT DOMAIN 154..304
FT /note="GAF 1"
FT DOMAIN 336..493
FT /note="GAF 2"
FT DOMAIN 526..850
FT /note="PDEase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01192"
FT ACT_SITE 603
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:O76083"
FT BINDING 607
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76074"
FT BINDING 643
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76074"
FT BINDING 644
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:O76074"
FT BINDING 644
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76074"
FT BINDING 754
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:O76074"
FT BINDING 807
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /evidence="ECO:0000250|UniProtKB:O76074"
FT MOD_RES 92
FT /note="Phosphoserine"
FT /evidence="ECO:0000255"
FT MUTAGEN 276
FT /note="N->A: Decreased cGMP-binding; no change in catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:8703039"
FT MUTAGEN 277
FT /note="K->A: Decreased cGMP-binding; no change in catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:8703039"
FT MUTAGEN 277
FT /note="K->R: Slight increase in cGMP-binding."
FT /evidence="ECO:0000269|PubMed:8703039"
FT MUTAGEN 289
FT /note="D->A: Decreased cGMP-binding; no change in catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:8530505,
FT ECO:0000269|PubMed:8703039, ECO:0000269|PubMed:9445376"
FT MUTAGEN 289
FT /note="D->N: Increased cGMP-binding; no change in catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:8530505,
FT ECO:0000269|PubMed:8703039, ECO:0000269|PubMed:9445376"
FT MUTAGEN 290
FT /note="E->A: No change in cGMP-binding."
FT /evidence="ECO:0000269|PubMed:8703039"
FT MUTAGEN 478
FT /note="D->A: Increased cGMP-binding; no change in catalytic
FT activity. Phosphorylated at lower concentrations of cGMP."
FT /evidence="ECO:0000269|PubMed:8530505,
FT ECO:0000269|PubMed:9445376"
SQ SEQUENCE 865 AA; 98627 MW; 2FF7144B2990B4F7 CRC64;
MERAGPGSAR PQQQWDQDSV EAWLDDHWDF TFSYFVRKGT REMVNAWFAE RVHTIPVCKE
GIKGHTESCS CPLQPSPRAE SSVPGTPTRK ISASEFDRPL RPIVIKDSEG TVSFLSDSDK
KEQMPLTSPR FDNDEGDQCS RLLELVKDIS SHLDVTALCH KIFLHIHGLI SADRYSLFLV
CEDSSNDKFL ISRLFDVAEG STLEEASNNC IRLEWNKGIV GHVAAFGEPL NIKDAYEDPR
FNAEVDQITG YKTQSILCMP IKNHREEVVG VAQAINKKSG NGGTFTEKDE KDFAAYLAFC
GIVLHNAQLY ETSLLENKRN QVLLDLASLI FEEQQSLEVI LKKIAATIIS FMQVQKCTIF
IVDEDCSDSF SSVFHMECEE LEKSSDTLTR ERDANRINYM YAQYVKNTME PLNIPDVSKD
KRFPWTNENM GNINQQCIRS LLCTPIKNGK KNKVIGVCQL VNKMEETTGK VKAFNRNDEQ
FLEAFVIFCG LGIQNTQMYE AVERAMAKQM VTLEVLSYHA SAAEEETREL QSLAAAVVPS
AQTLKITDFS FSDFELSDLE TALCTIRMFT DLNLVQNFQM KHEVLCKWIL SVKKNYRKNV
AYHNWRHAFN TAQCMFAALK AGKIQKRLTD LEILALLIAA LSHDLDHRGV NNSYIQRSEH
PLAQLYCHSI MEHHHFDQCL MILNSPGNQI LSGLSIEEYK TTLKIIKQAI LATDLALYIK
RRGEFFELIM KNQFNLEDPH QKELFLAMLM TACDLSAITK PWPIQQRIAE LVATEFFDQG
DRERKELNIE PADLMNREKK NKIPSMQVGF IDAICLQLYE ALTHVSEDCF PLLDGCRKNR
QKWQALAEQQ EKTLINGESS QTKRN
