P27815 (PDE4A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	886 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. Ref.13 Ref.18
Catalytic activity	Adenosine 3',5'-cyclic phosphate + H2O = adenosine 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. Ref.18
Enzyme regulation	Isoform 1, isoform 2, isoform 6 and isoform 7 are inhibited by rolipram and cilomilast. Isoform 1, isoform 2 and isoform 6 are inhibited by 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone (Ro 20-1724), roflumilast and denbufylline. Ref.5 Ref.6 Ref.7
Pathway	Purine metabolism; 3',5'-cyclic AMP degradation; AMP from 3',5'-cyclic AMP: step 1/1.
Subunit structure	Isoform 1 interacts with LYN. Isoform 2 and isoform 6 interact weakly with LYN. Isoform 1, isoform 2 and isoform 6 interact with ARRB2. Ref.5 Ref.6
Subcellular location	Isoform 1: Cytoplasm › perinuclear region Ref.5 Ref.6 Ref.7. Isoform 2: Cytoplasm › perinuclear region Ref.5 Ref.6 Ref.7. Cell projection › ruffle membrane Ref.5 Ref.6 Ref.7. Isoform 4: Membrane; Peripheral membrane protein. Note: Isoform 4 has propensity for association with membranes. Ref.5 Ref.6 Ref.7 Isoform 6: Cytoplasm › perinuclear region Ref.5 Ref.6 Ref.7. Isoform 7: Cytoplasm. Membrane. Note: Predominantly cytoplasmic. Ref.5 Ref.6 Ref.7
Tissue specificity	Isoform 1 is widely expressed. Isoform 2 is abundant in liver, stomach, testis, thyroid and adrenal glands. It is also found in placenta, kidney, pancreas, ovary, uterus, skin, monocytes, mast cells, macrophages, as well as in bronchial smooth muscle. Isoform 6 is expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes. Isoform 7 is expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Isoform 7 is expressed in the brain. Found in specific neuronal subpopulations in cortex, spinal cord and cerebellum (at protein level). Ref.5 Ref.6 Ref.7
Post-translational modification	Phosphorylation by MAPKAPK2 its activation through PKA phosphorylation By similarity. Phosphorylated at Ser-686 and Ser-688 when expressed in S.frugiperda cells. Isoform 2 and isoform 7 are activated by phosphorylation at Ser-119 and Ser-123 respectively by PKA. Ref.6 Ref.7 Ref.13 Proteolytically cleaved by caspase-3. Ref.6
Sequence similarities	Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.
Biophysicochemical properties	Kinetic parameters: KM=4.0 µM for cAMP (isoform 2) Ref.5 Ref.6 KM=3 µM for cAMP (isoform 6)

Ontologies

Keywords
Cellular component	Cell membrane Cell projection Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Ligand	Metal-binding cAMP
Molecular function	Hydrolase
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cAMP catabolic process Inferred from mutant phenotype PubMed 17704206. Source: UniProtKB cellular response to drug Inferred from electronic annotation. Source: Compara regulation of cAMP-mediated signaling Inferred from electronic annotation. Source: Compara regulation of protein kinase A signaling cascade Inferred from electronic annotation. Source: Compara sensory perception of smell Inferred from electronic annotation. Source: Compara signal transduction Traceable author statement PubMed 8940140. Source: ProtInc
Cellular_component	cytosol Traceable author statement. Source: Reactome membrane Traceable author statement Ref.4. Source: ProtInc perinuclear region of cytoplasm Inferred from direct assay Ref.5. Source: UniProtKB ruffle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	3',5'-cyclic-AMP phosphodiesterase activity Traceable author statement Ref.4. Source: ProtInc metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 7 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: P27815-1)

Also known as: PDE4A4; PDE4A4B; 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; PDE4A11;

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

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

Isoform 5 (identifier: P27815-5)

Also known as: PDE4A8A; 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: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Probably represents a non-functional splice isoform.

Isoform 6 (identifier: P27815-6)

Also known as: PDE4A10;

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

Isoform 7 (identifier: P27815-7)

Also known as: PDE4A8;

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

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

Nucleotide binding

433 – 437

5

cAMP By similarity

Region

330 – 723

394

Catalytic

Sites

Active site

433

1

Proton donor By similarity

Metal binding

437

1

Divalent metal cation 1

Metal binding

473

1

Divalent metal cation 1

Metal binding

474

1

Divalent metal cation 1

Metal binding

474

1

Divalent metal cation 2

Metal binding

591

1

Divalent metal cation 1

Binding site

474

1

cAMP By similarity

Binding site

591

1

cAMP By similarity

Binding site

642

1

cAMP By similarity

Site

69 – 70

2

Cleavage; by caspase-3

Site

594

1

Binds AMP, but not cAMP By similarity

Amino acid modifications

Modified residue

152

1

Phosphoserine; by MAPKAPK2 By similarity

Modified residue

165

1

Phosphoserine Ref.16

Modified residue

686

1

Phosphoserine Probable

Modified residue

688

1

Phosphoserine Probable

Cross-link

358

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.17

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

1 – 107

107

MEPPT…GSSRR → MRSGAAPRARPRPPALALPP TGPESLTHFPFSDEDTRRHP PGRSVS in isoform 6.

VSP_038185

Alternative sequence

1 – 107

107

MEPPT…GSSRR → MKRSRSALSVAGTGDERSRE TPESDRANMLGADLRRPRRR LSSGPGLGWAQPEPSDPGVP LPPRPTTLPLLIPPRISITR AENDS in isoform 7.

VSP_038186

Alternative sequence

644 – 657

14

GFIDY…LWETW → QARGIDGRAQGGFY in isoform 5.

VSP_004560

Alternative sequence

658 – 886

229

Missing in isoform 5.

VSP_004561

Natural variant

736

1

A → E. Ref.3 Ref.11
Corresponds to variant rs1051738 [ dbSNP | Ensembl ].

VAR_059544

Natural variant

808

1

H → Y.
Corresponds to variant rs2230190 [ dbSNP | Ensembl ].

VAR_059545

Secondary structure

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886

Helix Strand Turn

Details...

Helix

362 – 368

7

Helix

369 – 371

3

Helix

379 – 385

7

Turn

386 – 388

3

Helix

390 – 401

12

Helix

404 – 407

4

Helix

412 – 424

13

Beta strand

430 – 434

5

Helix

435 – 449

15

Helix

452 – 454

3

Turn

455 – 457

3

Helix

460 – 472

13

Turn

473 – 476

4

Helix

482 – 487

6

Helix

491 – 495

5

Turn

496 – 498

3

Helix

501 – 512

12

Helix

513 – 515

3

Turn

521 – 524

4

Helix

527 – 542

16

Helix

546 – 548

3

Helix

549 – 561

13

Beta strand

567 – 569

3

Helix

576 – 591

16

Helix

594 – 596

3

Helix

599 – 622

24

Turn

633 – 635

3

Helix

638 – 648

11

Helix

650 – 660

11

Turn

661 – 665

5

Helix

666 – 682

17

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (PDE4A4) (PDE4A4B) (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) (PDE4A11) [UniParc]. 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) [UniParc]. 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) [UniParc]. 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 (PDE4A8A) (2EL) [UniParc]. 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
	Isoform 6 (PDE4A10) [UniParc]. Checksum: B50A342801E605FB	FASTA	825	91,323
	10 20 30 40 50 60 MRSGAAPRAR PRPPALALPP TGPESLTHFP FSDEDTRRHP PGRSVSFEAE NGPTPSPGRS 70 80 90 100 110 120 PLDSQASPGL VLHAGAATSQ RRESFLYRSD SDYDMSPKTM SRNSSVTSEA HAEDLIVTPF 130 140 150 160 170 180 AQVLASLRSV RSNFSLLTNV PVPSNKRSPL GGPTPVCKAT LSEETCQQLA RETLEELDWC 190 200 210 220 230 240 LEQLETMQTY RSVSEMASHK FKRMLNRELT HLSEMSRSGN QVSEYISTTF LDKQNEVEIP 250 260 270 280 290 300 SPTMKEREKQ QAPRPRPSQP PPPPVPHLQP MSQITGLKKL MHSNSLNNSN IPRFGVKTDQ 310 320 330 340 350 360 EELLAQELEN LNKWGLNIFC VSDYAGGRSL TCIMYMIFQE RDLLKKFRIP VDTMVTYMLT 370 380 390 400 410 420 LEDHYHADVA YHNSLHAADV LQSTHVLLAT PALDAVFTDL EILAALFAAA IHDVDHPGVS 430 440 450 460 470 480 NQFLINTNSE LALMYNDESV LENHHLAVGF KLLQEDNCDI FQNLSKRQRQ SLRKMVIDMV 490 500 510 520 530 540 LATDMSKHMT LLADLKTMVE TKKVTSSGVL LLDNYSDRIQ VLRNMVHCAD LSNPTKPLEL 550 560 570 580 590 600 YRQWTDRIMA EFFQQGDRER ERGMEISPMC DKHTASVEKS QVGFIDYIVH PLWETWADLV 610 620 630 640 650 660 HPDAQEILDT LEDNRDWYYS AIRQSPSPPP EEESRGPGHP PLPDKFQFEL TLEEEEEEEI 670 680 690 700 710 720 SMAQIPCTAQ EALTAQGLSG VEEALDATIA WEASPAQESL EVMAQEASLE AELEAVYLTQ 730 740 750 760 770 780 QAQSTGSAPV APDEFSSREE FVVAVSHSSP SALALQSPLL PAWRTLSVSE HAPGLPGLPS 790 800 810 820 TAAEVEAQRE HQAAKRACSA CAGTFGEDTS ALPAPGGGGS GGDPT
	Isoform 7 (PDE4A8) [UniParc]. Checksum: 1AB6019FC85E37E4	FASTA	864	95,571
	10 20 30 40 50 60 MKRSRSALSV AGTGDERSRE TPESDRANML GADLRRPRRR LSSGPGLGWA QPEPSDPGVP 70 80 90 100 110 120 LPPRPTTLPL LIPPRISITR AENDSFEAEN GPTPSPGRSP LDSQASPGLV LHAGAATSQR 130 140 150 160 170 180 RESFLYRSDS DYDMSPKTMS RNSSVTSEAH AEDLIVTPFA QVLASLRSVR SNFSLLTNVP 190 200 210 220 230 240 VPSNKRSPLG GPTPVCKATL SEETCQQLAR ETLEELDWCL EQLETMQTYR SVSEMASHKF 250 260 270 280 290 300 KRMLNRELTH LSEMSRSGNQ VSEYISTTFL DKQNEVEIPS PTMKEREKQQ APRPRPSQPP 310 320 330 340 350 360 PPPVPHLQPM SQITGLKKLM HSNSLNNSNI PRFGVKTDQE ELLAQELENL NKWGLNIFCV 370 380 390 400 410 420 SDYAGGRSLT CIMYMIFQER DLLKKFRIPV DTMVTYMLTL EDHYHADVAY HNSLHAADVL 430 440 450 460 470 480 QSTHVLLATP ALDAVFTDLE ILAALFAAAI HDVDHPGVSN QFLINTNSEL ALMYNDESVL 490 500 510 520 530 540 ENHHLAVGFK LLQEDNCDIF QNLSKRQRQS LRKMVIDMVL ATDMSKHMTL LADLKTMVET 550 560 570 580 590 600 KKVTSSGVLL LDNYSDRIQV LRNMVHCADL SNPTKPLELY RQWTDRIMAE FFQQGDRERE 610 620 630 640 650 660 RGMEISPMCD KHTASVEKSQ VGFIDYIVHP LWETWADLVH PDAQEILDTL EDNRDWYYSA 670 680 690 700 710 720 IRQSPSPPPE EESRGPGHPP LPDKFQFELT LEEEEEEEIS MAQIPCTAQE ALTAQGLSGV 730 740 750 760 770 780 EEALDATIAW EASPAQESLE VMAQEASLEA ELEAVYLTQQ AQSTGSAPVA PDEFSSREEF 790 800 810 820 830 840 VVAVSHSSPS ALALQSPLLP AWRTLSVSEH APGLPGLPST AAEVEAQREH QAAKRACSAC 850 860 AGTFGEDTSA LPAPGGGGSG GDPT

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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
[3]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 5), VARIANT GLU-736.
[4]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2; 3; 4 AND 5). Tissue: Brain.
[5]	"Molecular cloning, genomic positioning, promoter identification, and characterization of the novel cyclic AMP-specific phosphodiesterase PDE4A10." Rena G., Begg F., Ross A., MacKenzie C., McPhee I., Campbell L., Huston E., Sullivan M., Houslay M.D. Mol. Pharmacol. 59:996-1011(2001) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6), SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, TISSUE SPECIFICITY, INTERACTION WITH LYN. Tissue: Brain.
[6]	"Identification and characterization of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cAMP phosphodiesterase gene." Wallace D.A., Johnston L.A., Huston E., Macmaster D., Houslay T.M., Cheung Y.-F., Campbell L., Millen J.E., Smith R.A., Gall I., Knowles R.G., Sullivan M., Houslay M.D. Mol. Pharmacol. 67:1920-1934(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), SUBCELLULAR LOCATION, TISSUE SPECIFICITY, ENZYME REGULATION, BIOPHYSICOCHEMICAL PROPERTIES, PHOSPHORYLATION AT SER-119 (ISOFORM 2), CLEAVAGE BY CASPASE-3 (ISOFORM 1), INTERACTION WITH LYN AND ARRB2.
[7]	"Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change." Mackenzie K.F., Topping E.C., Bugaj-Gaweda B., Deng C., Cheung Y.-F., Olsen A.E., Stockard C.R., High Mitchell L., Baillie G.S., Grizzle W.E., De Vivo M., Houslay M.D., Wang D., Bolger G.B. Biochem. J. 411:361-369(2008) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), SUBCELLULAR LOCATION, ENZYME REGULATION, TISSUE SPECIFICITY, PHOSPHORYLATION AT SER-123 (ISOFORM 7).
[8]	"The DNA sequence and biology of human chromosome 19." Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M. Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). Tissue: Brain.
[11]	"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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 112-886, VARIANT GLU-736. Tissue: Monocyte.
[12]	McLaughlin M.M. Submitted (JAN-1991) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION.
[13]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT SER-686 AND SER-688, MASS SPECTROMETRY.
[14]	"An unappreciated role for RNA surveillance." Hillman R.T., Green R.E., Brenner S.E. Genome Biol. 5:R8.1-R8.16(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[15]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[16]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-165, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[17]	"Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK." Li X., Vadrevu S., Dunlop A., Day J., Advant N., Troeger J., Klussmann E., Jaffrey E., Hay R.T., Adams D.R., Houslay M.D., Baillie G.S. Biochem. J. 428:55-65(2010) [PubMed] [Europe PMC] [Abstract] Cited for: SUMOYLATION AT LYS-358 BY PIAS4.
[18]	"Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors." Wang H., Peng M.-S., Chen Y., Geng J., Robinson H., Houslay M.D., Cai J., Ke H. Biochem. J. 408:193-201(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 351-683 IN COMPLEX WITH METAL IONS AND THE INHIBITOR NVP, FUNCTION, COFACTOR.
[19]	"Crystal structure of human PDE4a with 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone." Cheng R.K.Y., Crawley L., Barker J., Wood M., Felicetti B., Whittaker M. Submitted (JUL-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 351-683 IN COMPLEX WITH METAL IONS AND INHIBITOR.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L20965 mRNA. Translation: AAA03588.1.
S75213 mRNA. Translation: AAB33798.1.
U18087 mRNA. Translation: AAC50458.1.
U18088 mRNA. Translation: AAA98540.1.
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.
AF073745 mRNA. Translation: AAD34217.2.
AY618547 mRNA. Translation: AAU82096.1.
AY593872 mRNA. Translation: AAT00628.1.
AC011548 Genomic DNA. No translation available.
AC011529 Genomic DNA. No translation available.
AC011461 Genomic DNA. No translation available.
CH471106 Genomic DNA. Translation: EAW84104.1.
CH471106 Genomic DNA. Translation: EAW84105.1.
CH471106 Genomic DNA. Translation: EAW84108.1.
BC019864 mRNA. Translation: AAH19864.1.
BC038234 mRNA. Translation: AAH38234.1.
M37744 mRNA. Translation: AAA69697.1.

IPI

IPI00006232.
IPI00020973.
IPI00171460.
IPI00220048.
IPI00220052.
IPI00940499.
IPI00945522.

PIR

A54442.
S55348.

RefSeq

NP_001104777.1. NM_001111307.1.
NP_001104778.1. NM_001111308.1.
NP_001104779.1. NM_001111309.1.
NP_001230050.1. NM_001243121.1.
NP_006193.1. NM_006202.2.

UniGene

Hs.89901.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2QYK	X-ray	2.10	A/B	351-683	[»]
3I8V	X-ray	2.25	A/B	351-683	[»]
3TVX	X-ray	2.84	A/B	351-683	[»]

ProteinModelPortal

P27815.

ModBase

Search...

PTM databases

PhosphoSite

P27815.

Polymorphism databases

DMDM

116242706.

Proteomic databases

PaxDb

P27815.

PRIDE

P27815.

Protocols and materials databases

DNASU

5141.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000293683; ENSP00000293683; ENSG00000065989.
ENST00000344979; ENSP00000341007; ENSG00000065989.
ENST00000352831; ENSP00000270474; ENSG00000065989.
ENST00000380702; ENSP00000370078; ENSG00000065989.
ENST00000440014; ENSP00000394754; ENSG00000065989.
ENST00000592685; ENSP00000468507; ENSG00000065989.

GeneID

5141.

KEGG

hsa:5141.

UCSC

uc002moj.2. human.
uc002mok.2. human.
uc002mol.2. human.
uc002mom.2. human.
uc002moo.2. human.
uc021uow.1. human.

Organism-specific databases

CTD

5141.

GeneCards

GC19P010527.

HGNC

HGNC:8780. PDE4A.

HPA

CAB017632.

MIM

600126. gene.

neXtProt

NX_P27815.

PharmGKB

PA33128.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG122287.

HOVERGEN

HBG108239.

InParanoid

P27815.

KO

K01120.

OMA

HIPVDTM.

OrthoDB

EOG402WRM.

PhylomeDB

P27815.

Enzyme and pathway databases

Reactome

REACT_111102. Signal Transduction.

UniPathway

UPA00762; UER00747.

Gene expression databases

ArrayExpress

P27815.

Bgee

P27815.

CleanEx

HS_PDE4A.

Genevestigator

P27815.

GermOnline

ENSG00000065989. Homo sapiens.

Family and domain databases

Gene3D

1.10.1300.10. 1 hit.

InterPro

IPR003607. HD/PDEase_dom.
IPR023088. PDEase.
IPR002073. PDEase_catalytic_dom.
IPR023174. PDEase_CS.
[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

BindingDB

P27815.

ChEMBL

CHEMBL254.

ChiTaRS

PDE4A. human.

DrugBank

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

EvolutionaryTrace

P27815.

GenomeRNAi

5141.

NextBio

19824.

SOURCE

Search...

Entry information

Entry name

PDE4A_HUMAN

Accession

Primary (citable) accession number: P27815
Secondary accession number(s): O75522 , O76092, Q16255, Q16691, Q5DM53, Q6PMT2, Q8IVA7, Q8WUQ3, Q9H3H2

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1992
Last sequence update:	October 17, 2006
Last modified:	May 1, 2013
This is version 126 of the entry and version 3 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.