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Protein

cAMP-specific 3',5'-cyclic phosphodiesterase 4D

Gene

Pde4d

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

Catalytic activityi

Adenosine 3',5'-cyclic phosphate + H2O = adenosine 5'-phosphate.

Cofactori

a divalent metal cationBy similarityNote: 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

Enzyme regulationi

Activated by phosphatidic acid (By similarity). Inhibited by rolipram.By similarity1 Publication

Kineticsi

    1. Vmax=18 pmol/min/mg enzyme for cAMP (in the absence of follicle-stimulating hormone (FSH))1 Publication
    2. Vmax=5 pmol/min/mg enzyme for cAMP (in the presence of follicle-stimulating hormone (FSH))1 Publication

    Pathwayi: 3',5'-cyclic AMP degradation

    This protein is involved in step 1 of the subpathway that synthesizes AMP from 3',5'-cyclic AMP.
    Proteins known to be involved in this subpathway in this organism are:
    1. High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A (Pde7a), cAMP-specific 3',5'-cyclic phosphodiesterase 4D (Pde4d), cAMP-specific 3',5'-cyclic phosphodiesterase 4A (Pde4a), cAMP-specific 3',5'-cyclic phosphodiesterase 4B (Pde4b), cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (Pde10a), cAMP-specific 3',5'-cyclic phosphodiesterase 4C (Pde4c)
    This subpathway is part of the pathway 3',5'-cyclic AMP degradation, which is itself part of Purine metabolism.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes AMP from 3',5'-cyclic AMP, the pathway 3',5'-cyclic AMP degradation and in Purine metabolism.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei457Proton donorBy similarity1
    Metal bindingi461Divalent metal cation 1By similarity1
    Metal bindingi497Divalent metal cation 1By similarity1
    Metal bindingi498Divalent metal cation 1By similarity1
    Metal bindingi498Divalent metal cation 2By similarity1
    Binding sitei498cAMPBy similarity1
    Metal bindingi615Divalent metal cation 1By similarity1
    Sitei618Binds AMP, but not cAMPBy similarity1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi457 – 461cAMPBy similarity5

    GO - Molecular functioni

    • 3',5'-cyclic-nucleotide phosphodiesterase activity Source: InterPro
    • beta-2 adrenergic receptor binding Source: BHF-UCL
    • cyclic-nucleotide phosphodiesterase activity Source: RGD
    • enzyme binding Source: BHF-UCL
    • metal ion binding Source: UniProtKB-KW

    GO - Biological processi

    • adenylate cyclase-activating adrenergic receptor signaling pathway involved in positive regulation of heart rate Source: BHF-UCL
    • adrenergic receptor signaling pathway Source: BHF-UCL
    • cellular protein-containing complex assembly Source: RGD
    • establishment of endothelial barrier Source: UniProtKB
    • lung development Source: RGD
    • memory Source: RGD
    • positive regulation of cell-cell adhesion Source: RGD
    • positive regulation of protein phosphorylation Source: RGD
    • positive regulation of smooth muscle cell migration Source: RGD
    • positive regulation of smooth muscle cell proliferation Source: RGD
    • regulation of cAMP-mediated signaling Source: RGD
    • regulation of cardiac muscle cell contraction Source: BHF-UCL
    • regulation of G-protein coupled receptor protein signaling pathway Source: RGD
    • regulation of signaling receptor activity Source: BHF-UCL

    Keywordsi

    Molecular functionHydrolase
    LigandcAMP, Metal-binding

    Enzyme and pathway databases

    BRENDAi3.1.4.53 5301
    ReactomeiR-RNO-180024 DARPP-32 events
    R-RNO-418555 G alpha (s) signalling events
    UniPathwayiUPA00762; UER00747

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    cAMP-specific 3',5'-cyclic phosphodiesterase 4D (EC:3.1.4.53)
    Alternative name(s):
    DPDE3
    Gene namesi
    Name:Pde4d
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
    Proteomesi
    • UP000002494 Componenti: Chromosome 2

    Organism-specific databases

    RGDi3281 Pde4d

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Cytoskeleton, Membrane

    Pathology & Biotechi

    Chemistry databases

    ChEMBLiCHEMBL2712

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001988161 – 803cAMP-specific 3',5'-cyclic phosphodiesterase 4DAdd BLAST803

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei137PhosphoserineCombined sources1
    Modified residuei294PhosphoserineBy similarity1
    Modified residuei296PhosphoserineBy similarity1
    Modified residuei343PhosphoserineBy similarity1
    Modified residuei370PhosphoserineBy similarity1
    Cross-linki382Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)By similarity
    Isoform 5 (identifier: P14270-8)
    Modified residuei52PhosphoserineCombined sources1
    Modified residuei56PhosphoserineCombined sources1

    Post-translational modificationi

    Isoform 1 and isoform 9 are rapidly activated by PKA through phosphorylation. Long isoforms that share a conserved PKA phosphorylation site in the N-terminus are also activated.1 Publication
    Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation.By similarity

    Keywords - PTMi

    Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiP14270
    PRIDEiP14270

    PTM databases

    iPTMnetiP14270
    PhosphoSitePlusiP14270

    Expressioni

    Tissue specificityi

    Expressed in epithelial cells. Isoform 33, isoform 4, isoform 5 and isoform 9 are expressed in brain. Isoform 33, isoform 5, isoform 8 and isoform 9 are expressed in heart (at protein level). Isoform 4 and isoform 6 are strongly expressed in cortex and cerebellum. Isoform 7 is strongly expressed in cortex and testis; weakly expressed in kidney, lung, spleen and cerebellum. Isoform 8 is strongly expressed in lung, heart and liver. Isoform 31, isoform 32, isoform 33, isoform 5 and isoform 9 are widely distributed.2 Publications

    Inductioni

    Up-regulated by cAMP and follicle-stimulating hormone.1 Publication

    Gene expression databases

    BgeeiENSRNOG00000042536
    ExpressionAtlasiP14270 baseline and differential
    GenevisibleiP14270 RN

    Interactioni

    Subunit structurei

    Homodimer for the long isoforms. Isoforms with truncated N-termini are monomeric. Binds ARRB2. Isoform 33 is part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Interacts with PDE4DIP. Isoform 5 interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner. Isoform 33, isoform 4, isoform 7, isoform 8 and isoform 9 but not isoform 32 and isoform 6 interact with SHANK2. Isoform 31 interacts weakly with SHANK2.By similarity2 Publications

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    • beta-2 adrenergic receptor binding Source: BHF-UCL
    • enzyme binding Source: BHF-UCL

    Protein-protein interaction databases

    BioGridi246765, 4 interactors
    IntActiP14270, 3 interactors
    MINTiP14270
    STRINGi10116.ENSRNOP00000067171

    Structurei

    3D structure databases

    ProteinModelPortaliP14270
    SMRiP14270
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini381 – 710PDEasePROSITE-ProRule annotationAdd BLAST330

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiKOG3689 Eukaryota
    ENOG410XRI7 LUCA
    GeneTreeiENSGT00760000118889
    HOVERGENiHBG108239
    InParanoidiP14270
    KOiK13293
    OrthoDBiEOG091G06CD
    PhylomeDBiP14270

    Family and domain databases

    CDDicd00077 HDc, 1 hit
    Gene3Di1.10.1300.10, 1 hit
    InterProiView protein in InterPro
    IPR003607 HD/PDEase_dom
    IPR023088 PDEase
    IPR002073 PDEase_catalytic_dom
    IPR036971 PDEase_catalytic_dom_sf
    IPR023174 PDEase_CS
    PfamiView protein in Pfam
    PF00233 PDEase_I, 1 hit
    PRINTSiPR00387 PDIESTERASE1
    PROSITEiView protein in PROSITE
    PS00126 PDEASE_I_1, 1 hit
    PS51845 PDEASE_I_2, 1 hit

    Sequences (9)i

    Sequence statusi: Complete.

    This entry describes 9 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 4 (identifier: P14270-5) [UniParc]FASTAAdd to basket
    Also known as: PDE4D4

    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.

    « Hide

            10         20         30         40         50
    MEAEGSSVPA RAGSHEGSDS SGGAALKAPK HLWRHEQHHQ YPLRQPQFRL
    60 70 80 90 100
    LHPHHHLPPP PPPSPQPQLQ PPPPPPLPPP PPPPGATRGR YASSGASRVR
    110 120 130 140 150
    HRGYSDTERY LYCRAMDRTS YAVETGHRPG LKKSRMSWPS SFQGLRRFDV
    160 170 180 190 200
    DNGTSAGRSP LDPMTSPGSG LILQANFVHS QRRESFLYRS DSDYDLSPKS
    210 220 230 240 250
    MSRNSSIASD IHGDDLIVTP FAQVLASLRT VRNNFAALTN LQDRAPSKRS
    260 270 280 290 300
    PMCNQPSINK ATITEEAYQK LASETLEELD WCLDQLETLQ TRHSVSEMAS
    310 320 330 340 350
    NKFKRMLNRE LTHLSEMSRS GNQVSEYISN TFLDKQHEVE IPSPTQKEKE
    360 370 380 390 400
    KKKRPMSQIS GVKKLMHSSS LTNSCIPRFG VKTEQEDVLA KELEDVNKWG
    410 420 430 440 450
    LHVFRIAELS GNRPLTVIMH TIFQERDLLK TFKIPVDTLI TYLMTLEDHY
    460 470 480 490 500
    HADVAYHNNI HAADVVQSTH VLLSTPALEA VFTDLEILAA IFASAIHDVD
    510 520 530 540 550
    HPGVSNQFLI NTNSELALMY NDSSVLENHH LAVGFKLLQE ENCDIFQNLT
    560 570 580 590 600
    KKQRQSLRKM AIDIVLATDM SKHMNLLADL KTMVETKKVT SSGVLLLDNY
    610 620 630 640 650
    SDRIQVLQNM VHCADLSNPT KPLQLYRQWT DRIMEEFFRQ GDRERERGME
    660 670 680 690 700
    ISPMCDKHNA SVEKSQVGFI DYIVHPLWET WADLVHPDAQ DILDTLEDNR
    710 720 730 740 750
    EWYQSTIPQS PSPAPDDQED GRQGQTEKFQ FELTLEEDGE SDTEKDSGSQ
    760 770 780 790 800
    VEEDTSCSDS KTLCTQDSES TEIPLDEQVE EEAVAEEESQ PQTGVADDCC

    PDT
    Length:803
    Mass (Da):90,552
    Last modified:January 4, 2005 - v4
    Checksum:i13E28B257556496D
    GO
    Isoform 33 (identifier: P14270-1) [UniParc]FASTAAdd to basket
    Also known as: PDE4D3, PDE3.3

    The sequence of this isoform differs from the canonical sequence as follows:
         1-131: Missing.
         132-147: KKSRMSWPSSFQGLRR → MMHVNTFPFRRHSWIC

    Show »
    Length:672
    Mass (Da):76,263
    Checksum:i63CE38FA654A0BDD
    GO
    Isoform 31 (identifier: P14270-2) [UniParc]FASTAAdd to basket
    Also known as: PDE3.1

    The sequence of this isoform differs from the canonical sequence as follows:
         1-264: MEAEGSSVPA...QPSINKATIT → MKEQPSCAGT...TESPFPCLFA

    Show »
    Length:584
    Mass (Da):66,243
    Checksum:i7C0DAEB75774F2F8
    GO
    Isoform 32 (identifier: P14270-3) [UniParc]FASTAAdd to basket
    Also known as: PDE3.2

    The sequence of this isoform differs from the canonical sequence as follows:
         1-297: Missing.

    Show »
    Length:506
    Mass (Da):57,601
    Checksum:i7DCA5A564384FC34
    GO
    Isoform 5 (identifier: P14270-8) [UniParc]FASTAAdd to basket
    Also known as: PDE4D5

    The sequence of this isoform differs from the canonical sequence as follows:
         1-147: MEAEGSSVPA...WPSSFQGLRR → MAQQTTSPDT...QRRFTVAHTC

    Show »
    Length:745
    Mass (Da):84,335
    Checksum:i09DEADF7223F77BF
    GO
    Isoform 6 (identifier: P14270-7) [UniParc]FASTAAdd to basket
    Also known as: PDE4D6

    The sequence of this isoform differs from the canonical sequence as follows:
         1-286: Missing.
         287-301: ETLQTRHSVSEMASN → MPEANYLLSVSWGYI

    Show »
    Length:517
    Mass (Da):58,923
    Checksum:i251BF853D7CE6870
    GO
    Isoform 7 (identifier: P14270-4) [UniParc]FASTAAdd to basket
    Also known as: PDE4D7

    The sequence of this isoform differs from the canonical sequence as follows:
         1-56: Missing.
         57-147: LPPPPPPSPQ...WPSSFQGLRR → MERNTCDVLS...IAVTSADSTG

    Show »
    Length:747
    Mass (Da):84,430
    Checksum:iD63B9EF50AA3EFC9
    GO
    Isoform 8 (identifier: P14270-9) [UniParc]FASTAAdd to basket
    Also known as: PDE4D8

    The sequence of this isoform differs from the canonical sequence as follows:
         1-147: MEAEGSSVPA...WPSSFQGLRR → MAFVWDPLGVTVPGPSPRTRTRLRFSKSYS

    Show »
    Length:686
    Mass (Da):77,611
    Checksum:iD1F73EAEBDC6AA66
    GO
    Isoform 9 (identifier: P14270-6) [UniParc]FASTAAdd to basket
    Also known as: PDE4D9

    The sequence of this isoform differs from the canonical sequence as follows:
         1-125: Missing.
         126-147: GHRPGLKKSRMSWPSSFQGLRR → MSIIMKPRSRSTSSLRTTEAVC

    Show »
    Length:678
    Mass (Da):76,656
    Checksum:iE3069D16ADEBEC6C
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti226A → N in AAA56857 (PubMed:7958996).Curated1
    Sequence conflicti357S → P in AAQ90405 (Ref. 8) Curated1
    Sequence conflicti480 – 486Missing in AAA18924 (PubMed:8276818).Curated7
    Sequence conflicti480 – 486Missing in AAA18925 (PubMed:8276818).Curated7
    Sequence conflicti641G → E in AAC26969 (PubMed:7958996).Curated1
    Sequence conflicti757C → Y in AAA56857 (PubMed:7958996).Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0045821 – 297Missing in isoform 32. 1 PublicationAdd BLAST297
    Alternative sequenceiVSP_0124041 – 286Missing in isoform 6. 1 PublicationAdd BLAST286
    Alternative sequenceiVSP_0045811 – 264MEAEG…KATIT → MKEQPSCAGTGHPSMAGYGR MAPFELAGGPVKRLRTESPF PCLFA in isoform 31. 3 PublicationsAdd BLAST264
    Alternative sequenceiVSP_0534851 – 147MEAEG…QGLRR → MAQQTTSPDTLTVPEVDNPH VPNPWLNEDLVKSLRENLLQ HEKSKTARKSVSPKLSPVIS PRNSPRLLRRMLLSSNIPKQ RRFTVAHTC in isoform 5. 1 PublicationAdd BLAST147
    Alternative sequenceiVSP_0534861 – 147MEAEG…QGLRR → MAFVWDPLGVTVPGPSPRTR TRLRFSKSYS in isoform 8. 1 PublicationAdd BLAST147
    Alternative sequenceiVSP_0123981 – 131Missing in isoform 33. 2 PublicationsAdd BLAST131
    Alternative sequenceiVSP_0124021 – 125Missing in isoform 9. 1 PublicationAdd BLAST125
    Alternative sequenceiVSP_0124001 – 56Missing in isoform 7. 1 PublicationAdd BLAST56
    Alternative sequenceiVSP_01240157 – 147LPPPP…QGLRR → MERNTCDVLSRSKSASEETL HSCNDEEDPFRGMEPYLVRR LSSRSIQLPPLAFRQLEQTD LRSESENIPRPTSLPLKILP LIAVTSADSTG in isoform 7. 1 PublicationAdd BLAST91
    Alternative sequenceiVSP_012403126 – 147GHRPG…QGLRR → MSIIMKPRSRSTSSLRTTEA VC in isoform 9. 1 PublicationAdd BLAST22
    Alternative sequenceiVSP_012399132 – 147KKSRM…QGLRR → MMHVNTFPFRRHSWIC in isoform 33. 2 PublicationsAdd BLAST16
    Alternative sequenceiVSP_012405287 – 301ETLQT…EMASN → MPEANYLLSVSWGYI in isoform 6. 1 PublicationAdd BLAST15

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U09455 mRNA Translation: AAA20401.1
    U09457 mRNA Translation: AAB81869.1
    U09456 mRNA Translation: AAA20393.1
    U01280
    , U01278, U01282, U01283, U01284, U01285, U01286, U01287, U01279 Unassigned DNA Translation: AAA18925.1
    U01280
    , U01278, U01282, U01283, U01284, U01285, U01286, U01287, U01279 Unassigned DNA Translation: AAA18924.1
    AF031373 mRNA Translation: AAB95266.1
    AF536974 mRNA Translation: AAN10116.1
    EF102484 mRNA Translation: ABK97408.1
    EF121818 mRNA Translation: ABL14108.1
    AF536979 mRNA Translation: AAN10121.1
    AY388961 mRNA Translation: AAQ90405.1
    AABR06012736 Genomic DNA No translation available.
    AABR06012737 Genomic DNA No translation available.
    AABR06012738 Genomic DNA No translation available.
    AABR06012739 Genomic DNA No translation available.
    AABR06012740 Genomic DNA No translation available.
    AABR06012741 Genomic DNA No translation available.
    AABR06012742 Genomic DNA No translation available.
    AABR06012743 Genomic DNA No translation available.
    AABR06012744 Genomic DNA No translation available.
    AABR06012745 Genomic DNA No translation available.
    AABR06012746 Genomic DNA No translation available.
    AABR06012747 Genomic DNA No translation available.
    AABR06012748 Genomic DNA No translation available.
    AABR06012749 Genomic DNA No translation available.
    AABR06012750 Genomic DNA No translation available.
    AABR06012751 Genomic DNA No translation available.
    AABR06012752 Genomic DNA No translation available.
    AABR06012753 Genomic DNA No translation available.
    AABR06012754 Genomic DNA No translation available.
    AABR06012755 Genomic DNA No translation available.
    AABR06012756 Genomic DNA No translation available.
    AABR06012757 Genomic DNA No translation available.
    AABR06012758 Genomic DNA No translation available.
    AABR06012759 Genomic DNA No translation available.
    AABR06012760 Genomic DNA No translation available.
    L27059 mRNA Translation: AAA56857.1
    L27060 mRNA Translation: AAC26969.1
    PIRiB53109
    I61259
    RefSeqiNP_001106799.1, NM_001113328.1
    NP_001106800.1, NM_001113329.1 [P14270-4]
    NP_001106803.1, NM_001113332.1 [P14270-8]
    NP_001106805.1, NM_001113334.1 [P14270-9]
    NP_058728.1, NM_017032.1 [P14270-1]
    XP_008758943.1, XM_008760721.1 [P14270-6]
    XP_008758944.1, XM_008760722.2 [P14270-7]
    XP_008758945.1, XM_008760723.1 [P14270-3]
    UniGeneiRn.160519
    Rn.163460
    Rn.169992
    Rn.95959

    Genome annotation databases

    EnsembliENSRNOT00000066384; ENSRNOP00000063446; ENSRNOG00000042536 [P14270-9]
    ENSRNOT00000067546; ENSRNOP00000062384; ENSRNOG00000042536 [P14270-7]
    GeneIDi24627
    KEGGirno:24627

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    Entry informationi

    Entry nameiPDE4D_RAT
    AccessioniPrimary (citable) accession number: P14270
    Secondary accession number(s): A1E347
    , A1EC59, F1M1H7, O35470, Q6TRI0, Q8CG04, Q8CG06
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 1, 1990
    Last sequence update: January 4, 2005
    Last modified: July 18, 2018
    This is version 159 of the entry and version 4 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    2. SIMILARITY comments
      Index of protein domains and families

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