Reviewed, UniProtKB/Swiss-Prot P27815 (PDE4A_HUMAN)

Names and origin

Protein names

Recommended name:
    cAMP-specific 3',5'-cyclic phosphodiesterase 4A
    EC=3.1.4.17
Alternative name(s):
    DPDE2
    PDE46

Gene names

Name:	PDE4A
Synonyms:	DPDE2

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	886 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	Adenosine 3',5'-cyclic phosphate + H2O = adenosine 5'-phosphate.
Enzyme regulation	Inhibited by rolipram.
Pathway	Purine metabolism; cAMP degradation; AMP from cAMP: step 1/1.
Subcellular location	Isoform 4: Membrane; Peripheral membrane protein. Note: Isoform 4 has propensity for association with membranes.
Post-translational modification	Phosphorylated at Ser-686 and Ser-688 when expressed in S.frugiperda cells. Ref.8
Sequence similarities	Belongs to the cyclic nucleotide phosphodiesterase family.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Alternative splicing
Ligand	cAMP
Molecular function	Hydrolase
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	signal transduction Traceable author statement. Source: ProtInc
Cellular component	membrane Inferred from electronic annotation. Source: UniProtKB-SubCell membrane fraction Ref.2 Traceable author statement. Source: ProtInc soluble fraction Traceable author statement. Source: ProtInc
Molecular function	3',5'-cyclic-AMP phosphodiesterase activity Ref.2 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: P27815-1)

Also known as: PDE46;

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 2 (identifier: P27815-2)

Also known as: TM3;

The sequence of this isoform differs from the canonical sequence as follows:
     1-107: MEPPTVPSER...GGAGGGSSRR → MARPRGLGRI...LGRQAWAGAG

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoform 3 (identifier: P27815-3)

Also known as: PDE4A7; PDE4A6;

The sequence of this isoform differs from the canonical sequence as follows:
     1-209: MEPPTVPSER...NVPVPSNKRS → MCPFPVTTV

Isoform 4 (identifier: P27815-4)

Also known as: PDE4A1; RD1;

The sequence of this isoform differs from the canonical sequence as follows:
     1-261: MEPPTVPSER...RSVSEMASHK → MPLVDFFCETCSKPWLVGWWDQ

Note: Isoform 4 has propensity for association with membranes.

Isoform 5 (identifier: P27815-5)

Also known as: PDE4A8; 2EL;

The sequence of this isoform differs from the canonical sequence as follows:
     1-367: MEPPTVPSER...KTDQEELLAQ → MVLPSDQGFKLLGNVLQGPEPYRLLTSGLRLHQ
     644-657: GFIDYIVHPLWETW → QARGIDGRAQGGFY
     658-886: Missing.

Note: Probably represents a non-functional splice isoform.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 886	886	cAMP-specific 3',5'-cyclic phosphodiesterase 4A		PRO_0000198806
Regions
	Region	330 – 723	394	Catalytic
Amino acid modifications
	Modified residue	686	1	Phosphoserine Probable
	Modified residue	688	1	Phosphoserine Probable
Natural variations
	Alternative sequence	1 – 367	367	MEPPT…ELLAQ → MVLPSDQGFKLLGNVLQGPE PYRLLTSGLRLHQ in isoform 5.		VSP_004559
	Alternative sequence	1 – 261	261	MEPPT…MASHK → MPLVDFFCETCSKPWLVGWW DQ in isoform 4.		VSP_004558
	Alternative sequence	1 – 209	209	MEPPT…SNKRS → MCPFPVTTV in isoform 3.		VSP_004557
	Alternative sequence	1 – 107	107	MEPPT…GSSRR → MARPRGLGRIPELQLVAFPV AVAAEDEAFLPEPLAPRAPR RPRSPPSSPVFFASPSPTFR RRLRLLRSCQDLGRQAWAGA G in isoform 2.		VSP_004556
	Alternative sequence	644 – 657	14	GFIDY…LWETW → QARGIDGRAQGGFY in isoform 5.		VSP_004560
	Alternative sequence	658 – 886	229	Missing in isoform 5.		VSP_004561
Experimental info
	Sequence conflict	736	1	A → E in AAA69697. Ref.3
	Sequence conflict	736	1	A → E in AAC50458. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (PDE46) [UniParc]. Last modified October 17, 2006. Version 3. Checksum: 92BB9B98BED711E7	FASTA	886	98,143
	10 20 30 40 50 60 MEPPTVPSER SLSLSLPGPR EGQATLKPPP QHLWRQPRTP IRIQQRGYSD SAERAERERQ 70 80 90 100 110 120 PHRPIERADA MDTSDRPGLR TTRMSWPSSF HGTGTGSGGA GGGSSRRFEA ENGPTPSPGR 130 140 150 160 170 180 SPLDSQASPG LVLHAGAATS QRRESFLYRS DSDYDMSPKT MSRNSSVTSE AHAEDLIVTP 190 200 210 220 230 240 FAQVLASLRS VRSNFSLLTN VPVPSNKRSP LGGPTPVCKA TLSEETCQQL ARETLEELDW 250 260 270 280 290 300 CLEQLETMQT YRSVSEMASH KFKRMLNREL THLSEMSRSG NQVSEYISTT FLDKQNEVEI 310 320 330 340 350 360 PSPTMKEREK QQAPRPRPSQ PPPPPVPHLQ PMSQITGLKK LMHSNSLNNS NIPRFGVKTD 370 380 390 400 410 420 QEELLAQELE NLNKWGLNIF CVSDYAGGRS LTCIMYMIFQ ERDLLKKFRI PVDTMVTYML 430 440 450 460 470 480 TLEDHYHADV AYHNSLHAAD VLQSTHVLLA TPALDAVFTD LEILAALFAA AIHDVDHPGV 490 500 510 520 530 540 SNQFLINTNS ELALMYNDES VLENHHLAVG FKLLQEDNCD IFQNLSKRQR QSLRKMVIDM 550 560 570 580 590 600 VLATDMSKHM TLLADLKTMV ETKKVTSSGV LLLDNYSDRI QVLRNMVHCA DLSNPTKPLE 610 620 630 640 650 660 LYRQWTDRIM AEFFQQGDRE RERGMEISPM CDKHTASVEK SQVGFIDYIV HPLWETWADL 670 680 690 700 710 720 VHPDAQEILD TLEDNRDWYY SAIRQSPSPP PEEESRGPGH PPLPDKFQFE LTLEEEEEEE 730 740 750 760 770 780 ISMAQIPCTA QEALTAQGLS GVEEALDATI AWEASPAQES LEVMAQEASL EAELEAVYLT 790 800 810 820 830 840 QQAQSTGSAP VAPDEFSSRE EFVVAVSHSS PSALALQSPL LPAWRTLSVS EHAPGLPGLP 850 860 870 880 STAAEVEAQR EHQAAKRACS ACAGTFGEDT SALPAPGGGG SGGDPT
	Isoform 2 (TM3). Checksum: 6A4FC32E8AF7559D	FASTA	860	95,236
	10 20 30 40 50 60 MARPRGLGRI PELQLVAFPV AVAAEDEAFL PEPLAPRAPR RPRSPPSSPV FFASPSPTFR 70 80 90 100 110 120 RRLRLLRSCQ DLGRQAWAGA GFEAENGPTP SPGRSPLDSQ ASPGLVLHAG AATSQRRESF 130 140 150 160 170 180 LYRSDSDYDM SPKTMSRNSS VTSEAHAEDL IVTPFAQVLA SLRSVRSNFS LLTNVPVPSN 190 200 210 220 230 240 KRSPLGGPTP VCKATLSEET CQQLARETLE ELDWCLEQLE TMQTYRSVSE MASHKFKRML 250 260 270 280 290 300 NRELTHLSEM SRSGNQVSEY ISTTFLDKQN EVEIPSPTMK EREKQQAPRP RPSQPPPPPV 310 320 330 340 350 360 PHLQPMSQIT GLKKLMHSNS LNNSNIPRFG VKTDQEELLA QELENLNKWG LNIFCVSDYA 370 380 390 400 410 420 GGRSLTCIMY MIFQERDLLK KFRIPVDTMV TYMLTLEDHY HADVAYHNSL HAADVLQSTH 430 440 450 460 470 480 VLLATPALDA VFTDLEILAA LFAAAIHDVD HPGVSNQFLI NTNSELALMY NDESVLENHH 490 500 510 520 530 540 LAVGFKLLQE DNCDIFQNLS KRQRQSLRKM VIDMVLATDM SKHMTLLADL KTMVETKKVT 550 560 570 580 590 600 SSGVLLLDNY SDRIQVLRNM VHCADLSNPT KPLELYRQWT DRIMAEFFQQ GDRERERGME 610 620 630 640 650 660 ISPMCDKHTA SVEKSQVGFI DYIVHPLWET WADLVHPDAQ EILDTLEDNR DWYYSAIRQS 670 680 690 700 710 720 PSPPPEEESR GPGHPPLPDK FQFELTLEEE EEEEISMAQI PCTAQEALTA QGLSGVEEAL 730 740 750 760 770 780 DATIAWEASP AQESLEVMAQ EASLEAELEA VYLTQQAQST GSAPVAPDEF SSREEFVVAV 790 800 810 820 830 840 SHSSPSALAL QSPLLPAWRT LSVSEHAPGL PGLPSTAAEV EAQREHQAAK RACSACAGTF 850 860 GEDTSALPAP GGGGSGGDPT
	Isoform 3 (PDE4A7) (PDE4A6). Checksum: 35F0A712804410AF	FASTA	686	76,380
	10 20 30 40 50 60 MCPFPVTTVP LGGPTPVCKA TLSEETCQQL ARETLEELDW CLEQLETMQT YRSVSEMASH 70 80 90 100 110 120 KFKRMLNREL THLSEMSRSG NQVSEYISTT FLDKQNEVEI PSPTMKEREK QQAPRPRPSQ 130 140 150 160 170 180 PPPPPVPHLQ PMSQITGLKK LMHSNSLNNS NIPRFGVKTD QEELLAQELE NLNKWGLNIF 190 200 210 220 230 240 CVSDYAGGRS LTCIMYMIFQ ERDLLKKFRI PVDTMVTYML TLEDHYHADV AYHNSLHAAD 250 260 270 280 290 300 VLQSTHVLLA TPALDAVFTD LEILAALFAA AIHDVDHPGV SNQFLINTNS ELALMYNDES 310 320 330 340 350 360 VLENHHLAVG FKLLQEDNCD IFQNLSKRQR QSLRKMVIDM VLATDMSKHM TLLADLKTMV 370 380 390 400 410 420 ETKKVTSSGV LLLDNYSDRI QVLRNMVHCA DLSNPTKPLE LYRQWTDRIM AEFFQQGDRE 430 440 450 460 470 480 RERGMEISPM CDKHTASVEK SQVGFIDYIV HPLWETWADL VHPDAQEILD TLEDNRDWYY 490 500 510 520 530 540 SAIRQSPSPP PEEESRGPGH PPLPDKFQFE LTLEEEEEEE ISMAQIPCTA QEALTAQGLS 550 560 570 580 590 600 GVEEALDATI AWEASPAQES LEVMAQEASL EAELEAVYLT QQAQSTGSAP VAPDEFSSRE 610 620 630 640 650 660 EFVVAVSHSS PSALALQSPL LPAWRTLSVS EHAPGLPGLP STAAEVEAQR EHQAAKRACS 670 680 ACAGTFGEDT SALPAPGGGG SGGDPT
	Isoform 4 (PDE4A1) (RD1). Checksum: 622A0BA91B7AC938	FASTA	647	72,222
	10 20 30 40 50 60 MPLVDFFCET CSKPWLVGWW DQFKRMLNRE LTHLSEMSRS GNQVSEYIST TFLDKQNEVE 70 80 90 100 110 120 IPSPTMKERE KQQAPRPRPS QPPPPPVPHL QPMSQITGLK KLMHSNSLNN SNIPRFGVKT 130 140 150 160 170 180 DQEELLAQEL ENLNKWGLNI FCVSDYAGGR SLTCIMYMIF QERDLLKKFR IPVDTMVTYM 190 200 210 220 230 240 LTLEDHYHAD VAYHNSLHAA DVLQSTHVLL ATPALDAVFT DLEILAALFA AAIHDVDHPG 250 260 270 280 290 300 VSNQFLINTN SELALMYNDE SVLENHHLAV GFKLLQEDNC DIFQNLSKRQ RQSLRKMVID 310 320 330 340 350 360 MVLATDMSKH MTLLADLKTM VETKKVTSSG VLLLDNYSDR IQVLRNMVHC ADLSNPTKPL 370 380 390 400 410 420 ELYRQWTDRI MAEFFQQGDR ERERGMEISP MCDKHTASVE KSQVGFIDYI VHPLWETWAD 430 440 450 460 470 480 LVHPDAQEIL DTLEDNRDWY YSAIRQSPSP PPEEESRGPG HPPLPDKFQF ELTLEEEEEE 490 500 510 520 530 540 EISMAQIPCT AQEALTAQGL SGVEEALDAT IAWEASPAQE SLEVMAQEAS LEAELEAVYL 550 560 570 580 590 600 TQQAQSTGSA PVAPDEFSSR EEFVVAVSHS SPSALALQSP LLPAWRTLSV SEHAPGLPGL 610 620 630 640 PSTAAEVEAQ REHQAAKRAC SACAGTFGED TSALPAPGGG GSGGDPT
	Isoform 5 (PDE4A8) (2EL). Checksum: 14D0EEF3D6CD4BEE	FASTA	323	36,706
	10 20 30 40 50 60 MVLPSDQGFK LLGNVLQGPE PYRLLTSGLR LHQELENLNK WGLNIFCVSD YAGGRSLTCI 70 80 90 100 110 120 MYMIFQERDL LKKFRIPVDT MVTYMLTLED HYHADVAYHN SLHAADVLQS THVLLATPAL 130 140 150 160 170 180 DAVFTDLEIL AALFAAAIHD VDHPGVSNQF LINTNSELAL MYNDESVLEN HHLAVGFKLL 190 200 210 220 230 240 QEDNCDIFQN LSKRQRQSLR KMVIDMVLAT DMSKHMTLLA DLKTMVETKK VTSSGVLLLD 250 260 270 280 290 300 NYSDRIQVLR NMVHCADLSN PTKPLELYRQ WTDRIMAEFF QQGDRERERG MEISPMCDKH 310 320 TASVEKSQVQ ARGIDGRAQG GFY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs." Bolger G., Michaeli T., Martins T., St John T., Steiner B., Rodgers L., Riggs M., Wigler M., Ferguson K. Mol. Cell. Biol. 13:6558-6571(1993) [PubMed: 8413254] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Identification and characterization of the human homologue of the short PDE4A cAMP-specific phosphodiesterase 4A variant RD1 (PDE4A1) by analysis of the human HSPDE4A gene locus located at chromosome 19p13.2." Sullivan M., Rena G., Begg F., Gordon L., Olsen A.S., Houslay M.D. Biochem. J. 333:693-703(1998) [PubMed: 9677330] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 1; 2; 3; 4 AND 5). Tissue: Brain.
[3]	"Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase." Livi G.P., Kmetz P., McHale M.M., Cieslinski L.B., Sathe G.M., Taylor D.P., Davis R.L., Torphy T.J., Balcarek J.M. Mol. Cell. Biol. 10:2678-2686(1990) [PubMed: 2160582] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 112-886. Tissue: Monocyte.
[4]	McLaughlin M.M. Submitted (JAN-1991) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION.
[5]	"Molecular cloning of a novel splice variant of human type IVA (PDE-IVA) cyclic AMP phosphodiesterase and localization of the gene to the p13.2-q12 region of human chromosome 19." Horton Y.M., Sullivan M., Houslay M.D. Biochem. J. 308:683-691(1995) [PubMed: 7772058] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 5).
[6]	"Molecular cloning and expression, in both COS-1 cells and S. cerevisiae, of a human cytosolic type-IVA, cyclic AMP specific phosphodiesterase (hPDE-IVA-h6.1)." Sullivan M., Egerton M., Shakur Y., Marquardsen A., Houslay M.D. Cell. Signal. 6:793-812(1994) [PubMed: 7888306] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). Tissue: Brain.
[8]	"Purification and characterization of the human pde4a catalytic domain (pde4a(330-723)) expressed in sf9 cells." Lario P.I., Bobechko B., Bateman K., Kelly J., Vrielink A., Huang Z. Arch. Biochem. Biophys. 394:54-60(2001) [PubMed: 11566027] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-686 AND SER-688, MASS SPECTROMETRY.
[9]	"An unappreciated role for RNA surveillance." Hillman R.T., Green R.E., Brenner S.E. Genome Biol. 5:RESEARCH008.1-RESEARCH008.16(2004) [PubMed: 14759258] [Abstract] Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

L20965 mRNA. Translation: AAA03588.1.
AF069491 , AF069487, AF069489, AF069490 Genomic DNA. Translation: AAC35012.1.
AF069491, AF069489, AF069490 Genomic DNA. Translation: AAC35013.1.
AF069491, AF069489, AF069490 Genomic DNA. Translation: AAC35014.1.
AF069491 , AF069488, AF069489, AF069490 Genomic DNA. Translation: AAC35015.1.
U68532 mRNA. Translation: AAC63832.1.
U97584 mRNA. Translation: AAC25679.1.
M37744 mRNA. Translation: AAA69697.1.
U18087 mRNA. Translation: AAC50458.1.
U18088 mRNA. Translation: AAA98540.1.
S75213 mRNA. Translation: AAB33798.1.
BC019864 mRNA. Translation: AAH19864.1.

IPI

IPI00006232.
IPI00020973.
IPI00171460.
IPI00220048.
IPI00220052.

PIR

A54442.
S55348.

RefSeq

NP_001104777.1.

UniGene

Hs.89901

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2QYK	X-ray	2.10	A/B	351-683	[»]

ModBase

Search...

PTM databases

PhosphoSite

P27815.

Proteomic databases

PRIDE

P27815.

Genome annotation databases

Ensembl

ENSG00000065989. Homo sapiens. [Contig view]

GeneID

5141.

KEGG

hsa:5141.

Organism-specific databases

GeneCards

GC19P010392.

H-InvDB

HIX0014746.

HGNC

HGNC:8780. PDE4A.

HPA

CAB017632.

MIM

600126. gene.

PharmGKB

PA33128.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P27815.

HOVERGEN

P27815.

OMA

P27815. HIPVDTM.

Enzyme and pathway databases

BRENDA

3.1.4.17. 247.

Gene expression databases

ArrayExpress

P27815.

Bgee

P27815.

CleanEx

HS_PDE4A.

GermOnline

ENSG00000065989. Homo sapiens.

Family and domain databases

InterPro

IPR003607. Met-dep_phosphohydro_HD.
IPR002073. PDEase.
[Graphical view]

Pfam

PF00233. PDEase_I. 1 hit.
[Graphical view]

PRINTS

PR00387. PDIESTERASE1.

SMART

SM00471. HDc. 1 hit.
[Graphical view]

PROSITE

PS00126. PDEASE_I. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB01166. Cilostazol.
DB00975. Dipyridamole.
DB00651. Dyphylline.
DB00824. Enprofylline.
DB01088. Iloprost.
DB00235. Milrinone.
DB00806. Pentoxifylline.
DB00692. Phentolamine.
DB00820. Tadalafil.
DB00277. Theophylline.

NextBio

19824.

SOURCE

Search...

Entry information

Entry name

PDE4A_HUMAN

Accession

Primary (citable) accession number: P27815
Secondary accession number(s): O75522 , O76092, Q16255, Q16691, Q8WUQ3

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1992
Last sequence update:	October 17, 2006
Last modified:	June 16, 2009
This is version 88 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)