O00408 (PDE2A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
cGMP-dependent 3',5'-cyclic phosphodiesterase
EC=3.1.4.17

Alternative name(s):
Cyclic GMP-stimulated phosphodiesterase
Short name=CGS-PDE
Short name=cGSPDE

Gene names

Name:

PDE2A

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	941 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Ref.7 Ref.8
Catalytic activity	Nucleoside 3',5'-cyclic phosphate + H2O = nucleoside 5'-phosphate.
Cofactor	Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions, while site 2 has a preference for magnesium and/or manganese ions By similarity.
Subunit structure	Homodimer.
Subcellular location	Cell membrane; Lipid-anchor.
Tissue specificity	Expressed in brain and to a lesser extent in heart, placenta, lung, skeletal muscle, kidney and pancreas.
Domain	GAF 1 functions as a dimerization domain, whereas GAF 2 binds cGMP, which causes activation of the catalytic activity of the enzyme By similarity.
Miscellaneous	cGMP binds at an allosteric activator site By similarity.
Sequence similarities	Belongs to the cyclic nucleotide phosphodiesterase family. PDE2 subfamily. Contains 2 GAF domains.

Ontologies

Keywords
Cellular component	Cell membrane Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Repeat
Ligand	Metal-binding Nucleotide-binding cAMP cGMP cGMP-binding
Molecular function	Hydrolase
PTM	Lipoprotein Myristate Palmitate Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cAMP catabolic process Inferred from direct assay Ref.7. Source: UniProtKB cAMP-mediated signaling Inferred from mutant phenotype. Source: UniProtKB cGMP catabolic process Inferred from direct assay Ref.7Ref.8. Source: UniProtKB cGMP-mediated signaling Inferred from mutant phenotype. Source: UniProtKB cellular response to cGMP Inferred from direct assay Ref.8. Source: UniProtKB cellular response to drug Inferred from mutant phenotype Ref.7. Source: UniProtKB cellular response to granulocyte macrophage colony-stimulating factor stimulus Inferred from direct assay. Source: UniProtKB cellular response to macrophage colony-stimulating factor stimulus Inferred from direct assay. Source: UniProtKB cellular response to mechanical stimulus Inferred from sequence or structural similarity. Source: UniProtKB cellular response to transforming growth factor beta stimulus Inferred from expression pattern. Source: UniProtKB establishment of endothelial barrier Inferred from sequence or structural similarity. Source: UniProtKB monocyte differentiation Inferred from expression pattern. Source: UniProtKB negative regulation of cAMP biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of protein import into nucleus, translocation Inferred from direct assay. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay. Source: UniProtKB negative regulation of vascular permeability Inferred from mutant phenotype. Source: UniProtKB platelet activation Traceable author statement. Source: Reactome positive regulation of inflammatory response Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of vascular permeability Inferred from mutant phenotype. Source: UniProtKB protein targeting to mitochondrion Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	Golgi apparatus Inferred from sequence or structural similarity. Source: UniProtKB cytosol Inferred from direct assay. Source: UniProtKB endoplasmic reticulum Inferred from sequence or structural similarity. Source: UniProtKB mitochondrial matrix Inferred from sequence or structural similarity. Source: UniProtKB nucleus Inferred from direct assay. Source: UniProtKB perinuclear region of cytoplasm Inferred from direct assay. Source: UniProtKB plasma membrane Inferred from direct assay. Source: UniProtKB presynaptic membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	TPR domain binding Inferred from physical interaction. Source: UniProtKB cAMP binding Inferred from mutant phenotype Ref.7. Source: UniProtKB cGMP binding Inferred from direct assay Ref.8. Source: UniProtKB cGMP-stimulated cyclic-nucleotide phosphodiesterase activity Inferred from direct assay. Source: UniProtKB calcium channel activity Traceable author statement. Source: UniProtKB drug binding Inferred from direct assay Ref.7. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein homodimerization activity Inferred from physical interaction Ref.8. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
AIP	O00170	6	EBI-1785967,EBI-704197

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist. Experimental confirmation may be lacking for some isoforms.

Isoform PDE2A3 (identifier: O00408-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform PDE2A1 (identifier: O00408-2)

The sequence of this isoform is not available.

Note: Soluble form.

Isoform PDE2A2 (identifier: O00408-3)

The sequence of this isoform is not available.

Isoform PDE2A4 (identifier: O00408-4)

The sequence of this isoform differs from the canonical sequence as follows:
     1-24: MGQACGHSILCRSQQYPAARPAEP → MKKQRIQEGKSLAHR

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 941

940

cGMP-dependent 3',5'-cyclic phosphodiesterase

PRO_0000198796

Regions

Domain

241 – 377

137

GAF 1

Domain

409 – 548

140

GAF 2

Region

633 – 891

259

Catalytic By similarity

Region

656 – 660

5

Substrate binding

Sites

Active site

656

1

Proton donor By similarity

Metal binding

660

1

Divalent metal cation 1

Metal binding

696

1

Divalent metal cation 1

Metal binding

697

1

Divalent metal cation 1

Metal binding

697

1

Divalent metal cation 2

Metal binding

808

1

Divalent metal cation 1

Binding site

431

1

cGMP By similarity

Binding site

446

1

cGMP By similarity

Binding site

499

1

cGMP By similarity

Binding site

697

1

Substrate

Binding site

808

1

Substrate

Amino acid modifications

Modified residue

909

1

Phosphoserine Ref.5

Lipidation

2

1

N-myristoyl glycine Ref.6

Lipidation

5

1

N-palmitoyl cysteine Probable

Lipidation

11

1

N-palmitoyl cysteine Probable

Natural variations

Alternative sequence

1 – 24

24

MGQAC…RPAEP → MKKQRIQEGKSLAHR in isoform PDE2A4.

VSP_042213

Natural variant

224

1

T → I.
Corresponds to variant rs341047 [ dbSNP | Ensembl ].

VAR_024170

Experimental info

Sequence conflict

38

1

P → L in AAS75513. Ref.2

Sequence conflict

213

1

T → A in AAS75513. Ref.2

Sequence conflict

664

1

V → A in AAS75513. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

941

Helix Strand Turn

Details...

Helix

580 – 585

6

Turn

586 – 588

3

Helix

593 – 595

3

Turn

598 – 601

4

Helix

607 – 609

3

Helix

612 – 614

3

Helix

615 – 625

11

Helix

628 – 631

4

Helix

636 – 648

13

Beta strand

654 – 657

4

Helix

658 – 675

18

Helix

677 – 679

3

Helix

683 – 695

13

Turn

696 – 699

4

Helix

705 – 710

6

Helix

714 – 719

6

Helix

720 – 722

3

Helix

725 – 738

14

Turn

745 – 748

4

Helix

751 – 766

16

Helix

770 – 786

17

Helix

793 – 808

16

Helix

810 – 813

4

Helix

816 – 839

24

Helix

846 – 848

3

Turn

850 – 852

3

Helix

855 – 865

11

Helix

867 – 877

11

Helix

879 – 881

3

Helix

882 – 896

15

Beta strand

904 – 906

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform PDE2A3 [UniParc]. Last modified July 1, 1997. Version 1. Checksum: 9797609B487FD64E	FASTA	941	105,717
	10 20 30 40 50 60 MGQACGHSIL CRSQQYPAAR PAEPRGQQVF LKPDEPPPPP QPCADSLQDA LLSLGSVIDI 70 80 90 100 110 120 SGLQRAVKEA LSAVLPRVET VYTYLLDGES QLVCEDPPHE LPQEGKVREA IISQKRLGCN 130 140 150 160 170 180 GLGFSDLPGK PLARLVAPLA PDTQVLVMPL ADKEAGAVAA VILVHCGQLS DNEEWSLQAV 190 200 210 220 230 240 EKHTLVALRR VQVLQQRGPR EAPRAVQNPP EGTAEDQKGG AAYTDRDRKI LQLCGELYDL 250 260 270 280 290 300 DASSLQLKVL QYLQQETRAS RCCLLLVSED NLQLSCKVIG DKVLGEEVSF PLTGCLGQVV 310 320 330 340 350 360 EDKKSIQLKD LTSEDVQQLQ SMLGCELQAM LCVPVISRAT DQVVALACAF NKLEGDLFTD 370 380 390 400 410 420 EDEHVIQHCF HYTSTVLTST LAFQKEQKLK CECQALLQVA KNLFTHLDDV SVLLQEIITE 430 440 450 460 470 480 ARNLSNAEIC SVFLLDQNEL VAKVFDGGVV DDESYEIRIP ADQGIAGHVA TTGQILNIPD 490 500 510 520 530 540 AYAHPLFYRG VDDSTGFRTR NILCFPIKNE NQEVIGVAEL VNKINGPWFS KFDEDLATAF 550 560 570 580 590 600 SIYCGISIAH SLLYKKVNEA QYRSHLANEM MMYHMKVSDD EYTKLLHDGI QPVAAIDSNF 610 620 630 640 650 660 ASFTYTPRSL PEDDTSMAIL SMLQDMNFIN NYKIDCPTLA RFCLMVKKGY RDPPYHNWMH 670 680 690 700 710 720 AFSVSHFCYL LYKNLELTNY LEDIEIFALF ISCMCHDLDH RGTNNSFQVA SKSVLAALYS 730 740 750 760 770 780 SEGSVMERHH FAQAIAILNT HGCNIFDHFS RKDYQRMLDL MRDIILATDL AHHLRIFKDL 790 800 810 820 830 840 QKMAEVGYDR NNKQHHRLLL CLLMTSCDLS DQTKGWKTTR KIAELIYKEF FSQGDLEKAM 850 860 870 880 890 900 GNRPMEMMDR EKAYIPELQI SFMEHIAMPI YKLLQDLFPK AAELYERVAS NREHWTKVSH 910 920 930 940 KFTIRGLPSN NSLDFLDEEY EVPDLDGTRA PINGCCSLDA E
	Isoform PDE2A1 (Sequence not available).		–	–
	Isoform PDE2A2 (Sequence not available).		–	–
	Isoform PDE2A4 [UniParc]. Checksum: 9F5CE92BA3C2E2E5	FASTA	932	104,955
	10 20 30 40 50 60 MKKQRIQEGK SLAHRRGQQV FLKPDEPPPP PQPCADSLQD ALLSLGSVID ISGLQRAVKE 70 80 90 100 110 120 ALSAVLPRVE TVYTYLLDGE SQLVCEDPPH ELPQEGKVRE AIISQKRLGC NGLGFSDLPG 130 140 150 160 170 180 KPLARLVAPL APDTQVLVMP LADKEAGAVA AVILVHCGQL SDNEEWSLQA VEKHTLVALR 190 200 210 220 230 240 RVQVLQQRGP REAPRAVQNP PEGTAEDQKG GAAYTDRDRK ILQLCGELYD LDASSLQLKV 250 260 270 280 290 300 LQYLQQETRA SRCCLLLVSE DNLQLSCKVI GDKVLGEEVS FPLTGCLGQV VEDKKSIQLK 310 320 330 340 350 360 DLTSEDVQQL QSMLGCELQA MLCVPVISRA TDQVVALACA FNKLEGDLFT DEDEHVIQHC 370 380 390 400 410 420 FHYTSTVLTS TLAFQKEQKL KCECQALLQV AKNLFTHLDD VSVLLQEIIT EARNLSNAEI 430 440 450 460 470 480 CSVFLLDQNE LVAKVFDGGV VDDESYEIRI PADQGIAGHV ATTGQILNIP DAYAHPLFYR 490 500 510 520 530 540 GVDDSTGFRT RNILCFPIKN ENQEVIGVAE LVNKINGPWF SKFDEDLATA FSIYCGISIA 550 560 570 580 590 600 HSLLYKKVNE AQYRSHLANE MMMYHMKVSD DEYTKLLHDG IQPVAAIDSN FASFTYTPRS 610 620 630 640 650 660 LPEDDTSMAI LSMLQDMNFI NNYKIDCPTL ARFCLMVKKG YRDPPYHNWM HAFSVSHFCY 670 680 690 700 710 720 LLYKNLELTN YLEDIEIFAL FISCMCHDLD HRGTNNSFQV ASKSVLAALY SSEGSVMERH 730 740 750 760 770 780 HFAQAIAILN THGCNIFDHF SRKDYQRMLD LMRDIILATD LAHHLRIFKD LQKMAEVGYD 790 800 810 820 830 840 RNNKQHHRLL LCLLMTSCDL SDQTKGWKTT RKIAELIYKE FFSQGDLEKA MGNRPMEMMD 850 860 870 880 890 900 REKAYIPELQ ISFMEHIAMP IYKLLQDLFP KAAELYERVA SNREHWTKVS HKFTIRGLPS 910 920 930 NNSLDFLDEE YEVPDLDGTR APINGCCSLD AE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3',5'-cyclic nucleotide phosphodiesterase." Rosman G.J., Martins T.J., Sonnenburg W.K., Beavo J.A., Ferguson K., Loughney K. Gene 191:89-95(1997) [PubMed: 9210593] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE2A3). Tissue: Fetal brain and Hippocampus.
[2]	"Human PDE2A4." Bugaj-Gaweda B., De Vivo M., Wang D. Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM PDE2A4).
[3]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed: 16554811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"Dual acylation of PDE2A splice variant 3: targeting to synaptic membranes." Russwurm C., Zoidl G., Koesling D., Russwurm M. J. Biol. Chem. 284:25782-25790(2009) [PubMed: 19632989] [Abstract] Cited for: MYRISTOYLATION AT GLY-2, PALMITOYLATION AT CYS-5 AND CYS-11, SUBCELLULAR LOCATION.
[5]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-909, MASS SPECTROMETRY.
[6]	"Strategy for comprehensive identification of human N-myristoylated proteins using an insect cell-free protein synthesis system." Suzuki T., Moriya K., Nagatoshi K., Ota Y., Ezure T., Ando E., Tsunasawa S., Utsumi T. Proteomics 10:1780-1793(2010) [PubMed: 20213681] [Abstract] Cited for: MYRISTOYLATION AT GLY-2.
[7]	"Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system." Iffland A., Kohls D., Low S., Luan J., Zhang Y., Kothe M., Cao Q., Kamath A.V., Ding Y.H., Ellenberger T. Biochemistry 44:8312-8325(2005) [PubMed: 15938621] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 578-919 IN COMPLEX WITH METAL IONS AND PHOSPHATE, FUNCTION.
[8]	"Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct." Pandit J., Forman M.D., Fennell K.F., Dillman K.S., Menniti F.S. Proc. Natl. Acad. Sci. U.S.A. 106:18225-18230(2009) [PubMed: 19828435] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 215-919 IN COMPLEX WITH METAL IONS AND THE INHIBITOR IBMX, SUBUNIT, FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U67733 mRNA. Translation: AAC51320.1.
AY495087 mRNA. Translation: AAS75513.1.
AP003065 Genomic DNA. No translation available.
AP005019 Genomic DNA. No translation available.

IPI

IPI00451132.

RefSeq

NP_001137311.1. NM_001143839.3.
NP_001139681.1. NM_001146209.2.
NP_001230713.1. NM_001243784.1.
NP_002590.1. NM_002599.4.

UniGene

Hs.503163.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1Z1L	X-ray	1.70	A	578-919	[»]
3IBJ	X-ray	3.02	A/B	215-900	[»]
3ITM	X-ray	2.49	A/B/C/D	579-919	[»]
3ITU	X-ray	1.58	A/B/C/D	579-919	[»]

ProteinModelPortal

O00408.

SMR

O00408. Positions 223-916.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-40269N.

IntAct

O00408. 3 interactions.

STRING

O00408.

PTM databases

PhosphoSite

O00408.

Proteomic databases

PRIDE

O00408.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000334456; ENSP00000334910; ENSG00000186642.

GeneID

5138.

KEGG

hsa:5138.

UCSC

uc001osm.1. human.

Organism-specific databases

CTD

5138.

GeneCards

GC11M072287.

H-InvDB

HIX0009909.

HGNC

HGNC:8777. PDE2A.

HPA

CAB009752.

MIM

602658. gene.

neXtProt

NX_O00408.

PharmGKB

PA33125.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG08500.

HOVERGEN

HBG053540.

InParanoid

O00408.

OrthoDB

EOG4THVS9.

PhylomeDB

O00408.

Enzyme and pathway databases

Reactome

REACT_111102. Signal Transduction.
REACT_604. Hemostasis.

Gene expression databases

Bgee

O00408.

CleanEx

HS_PDE2A.

Genevestigator

O00408.

GermOnline

ENSG00000186642. Homo sapiens.

Family and domain databases

InterPro

IPR003018. GAF.
IPR003607. Metal-dep_PHydrolase_HD_dom.
IPR023088. PDEase.
IPR002073. PDEase_catalytic_dom.
IPR023174. PDEase_CS.
[Graphical view]

Gene3D

G3DSA:1.10.1300.10. PDEase_catalytic_dom. 1 hit.

KO

K01120.

Pfam

PF01590. GAF. 2 hits.
PF00233. PDEase_I. 1 hit.
[Graphical view]

PRINTS

PR00387. PDIESTERASE1.

SMART

SM00065. GAF. 2 hits.
SM00471. HDc. 1 hit.
[Graphical view]

PROSITE

PS00126. PDEASE_I. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00203. Sildenafil.
DB00605. Sulindac.

NextBio

19812.

SOURCE

Search...

Entry information

Entry name

PDE2A_HUMAN

Accession

Primary (citable) accession number: O00408
Secondary accession number(s): E9PGI1, Q5J793

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	July 1, 1997
Last modified:	January 25, 2012
This is version 100 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.