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Protein

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

Gene

PDE4D

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.2 Publications

Catalytic activityi

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

Cofactori

a divalent metal cation2 PublicationsNote: 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.2 Publications

Enzyme regulationi

Inhibited by rolipram. Activated by phosphatidic acid.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. cAMP-specific 3',5'-cyclic phosphodiesterase 4C (PDE4C), cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A (PDE10A), cAMP-specific 3',5'-cyclic phosphodiesterase 4A (PDE4A), High affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A (PDE7A), cAMP-specific 3',5'-cyclic phosphodiesterase 7B (PDE7B), cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D), cAMP-specific 3',5'-cyclic phosphodiesterase 4B (PDE4B), High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A (PDE8A), High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B (PDE8B)
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 sitei462Proton donorBy similarity1
Metal bindingi466Divalent metal cation 11
Metal bindingi502Divalent metal cation 11
Metal bindingi503Divalent metal cation 11
Metal bindingi503Divalent metal cation 21
Binding sitei503cAMP2 Publications1
Metal bindingi620Divalent metal cation 11
Binding sitei620cAMP2 Publications1
Sitei623Binds AMP, but not cAMP1
Binding sitei671cAMP2 Publications1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi462 – 466cAMP2 Publications5

GO - Molecular functioni

  • 3',5'-cyclic-AMP phosphodiesterase activity Source: BHF-UCL
  • 3',5'-cyclic-nucleotide phosphodiesterase activity Source: UniProtKB
  • ATPase binding Source: BHF-UCL
  • beta-2 adrenergic receptor binding Source: BHF-UCL
  • cAMP binding Source: BHF-UCL
  • drug binding Source: UniProtKB
  • enzyme binding Source: BHF-UCL
  • ion channel binding Source: BHF-UCL
  • metal ion binding Source: UniProtKB-KW
  • scaffold protein binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: BHF-UCL

GO - Biological processi

  • adrenergic receptor signaling pathway Source: BHF-UCL
  • adrenergic receptor signaling pathway involved in positive regulation of heart rate Source: BHF-UCL
  • aging Source: Ensembl
  • cAMP catabolic process Source: BHF-UCL
  • cAMP-mediated signaling Source: BHF-UCL
  • cellular response to cAMP Source: BHF-UCL
  • cellular response to epinephrine stimulus Source: BHF-UCL
  • cellular response to lipopolysaccharide Source: Ensembl
  • establishment of endothelial barrier Source: UniProtKB
  • multicellular organism growth Source: Ensembl
  • negative regulation of heart contraction Source: BHF-UCL
  • negative regulation of peptidyl-serine phosphorylation Source: BHF-UCL
  • negative regulation of relaxation of cardiac muscle Source: BHF-UCL
  • neutrophil chemotaxis Source: Ensembl
  • positive regulation of interferon-gamma production Source: BHF-UCL
  • positive regulation of interleukin-2 production Source: BHF-UCL
  • positive regulation of interleukin-5 production Source: BHF-UCL
  • regulation of cAMP metabolic process Source: Ensembl
  • regulation of cardiac muscle cell contraction Source: BHF-UCL
  • regulation of cell communication by electrical coupling involved in cardiac conduction Source: BHF-UCL
  • regulation of heart rate Source: BHF-UCL
  • regulation of receptor activity Source: BHF-UCL
  • regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum Source: BHF-UCL
  • regulation of ryanodine-sensitive calcium-release channel activity Source: BHF-UCL
  • smooth muscle contraction Source: Ensembl
  • T cell receptor signaling pathway Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Ligandi

cAMP, Metal-binding

Enzyme and pathway databases

BioCyciZFISH:HS03683-MONOMER.
BRENDAi3.1.4.53. 2681.
ReactomeiR-HSA-180024. DARPP-32 events.
R-HSA-418555. G alpha (s) signalling events.
SignaLinkiQ08499.
SIGNORiQ08499.
UniPathwayiUPA00762; UER00747.

Names & Taxonomyi

Protein namesi
Recommended name:
cAMP-specific 3',5'-cyclic phosphodiesterase 4D (EC:3.1.4.53)
Alternative name(s):
DPDE3
PDE43
Gene namesi
Name:PDE4D
Synonyms:DPDE3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

HGNCiHGNC:8783. PDE4D.

Subcellular locationi

GO - Cellular componenti

  • apical plasma membrane Source: UniProtKB-SubCell
  • calcium channel complex Source: BHF-UCL
  • centrosome Source: Ensembl
  • cytosol Source: BHF-UCL
  • membrane Source: BHF-UCL
  • voltage-gated calcium channel complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Cytoskeleton, Membrane

Pathology & Biotechi

Involvement in diseasei

Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution.

Acrodysostosis 2, with or without hormone resistance (ACRDYS2)4 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems.
See also OMIM:614613
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_068242190S → A in ACRDYS2. 1 PublicationCorresponds to variant rs397514466dbSNPEnsembl.1
Natural variantiVAR_068243225P → T in ACRDYS2. 2 PublicationsCorresponds to variant rs397514464dbSNPEnsembl.1
Natural variantiVAR_068244226F → S in ACRDYS2. 1 PublicationCorresponds to variant rs397514465dbSNPEnsembl.1
Natural variantiVAR_069448227A → S in ACRDYS2. 1 Publication1
Natural variantiVAR_069449228Q → E in ACRDYS2. 1 PublicationCorresponds to variant rs397514468dbSNPEnsembl.1
Natural variantiVAR_069450301S → T in ACRDYS2. 1 Publication1
Natural variantiVAR_069451304A → V in ACRDYS2. 1 PublicationCorresponds to variant rs397515433dbSNPEnsembl.1
Natural variantiVAR_069452329V → A in ACRDYS2. 1 Publication1
Natural variantiVAR_068245587T → P in ACRDYS2. 1 PublicationCorresponds to variant rs397514467dbSNPEnsembl.1
Natural variantiVAR_069453590E → A in ACRDYS2. 2 Publications1
Natural variantiVAR_069454673G → D in ACRDYS2. 1 PublicationCorresponds to variant rs397514469dbSNPEnsembl.1
Natural variantiVAR_069455678I → T in ACRDYS2. 1 PublicationCorresponds to variant rs587777188dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi503D → N: Abolishes catalytic activity. 1
Mutagenesisi527D → R: Abolishes homodimerization. 1 Publication1
Mutagenesisi563R → D: Abolishes homodimerization. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi5144.
MalaCardsiPDE4D.
MIMi614613. phenotype.
OpenTargetsiENSG00000113448.
Orphaneti950. Acrodysostosis.
280651. Acrodysostosis with multiple hormone resistance.
PharmGKBiPA33130.

Chemistry databases

ChEMBLiCHEMBL288.
DrugBankiDB00131. Adenosine monophosphate.
DB05676. Apremilast.
DB00201. Caffeine.
DB00651. Dyphylline.
DB05266. Ibudilast.
DB01088. Iloprost.
DB00920. Ketotifen.
DB01656. Roflumilast.
GuidetoPHARMACOLOGYi1303.

Polymorphism and mutation databases

BioMutaiPDE4D.
DMDMi12644392.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001988141 – 809cAMP-specific 3',5'-cyclic phosphodiesterase 4DAdd BLAST809

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei142PhosphoserineBy similarity1
Modified residuei299PhosphoserineCombined sources1
Modified residuei301PhosphoserineCombined sources1
Modified residuei348PhosphoserineCombined sources1
Modified residuei375PhosphoserineCombined sources1
Cross-linki387Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)
Isoform 3 (identifier: Q08499-2)
Modified residuei53Phosphoserine1 Publication1
Isoform 5 (identifier: Q08499-6)
Modified residuei59PhosphoserineCombined sources1
Modified residuei63PhosphoserineCombined sources1
Isoform N3 (identifier: Q08499-7)
Modified residuei59PhosphoserineCombined sources1
Modified residuei63PhosphoserineCombined sources1
Isoform 12 (identifier: Q08499-12)
Modified residuei59PhosphoserineCombined sources1
Modified residuei63PhosphoserineCombined sources1

Post-translational modificationi

Long isoforms that share a conserved PKA phosphorylation site in the N-terminus are activated by PKA through phosphorylation (By similarity). Isoform 3 and isoform 7 are activated by phosphorylation (in vitro), but not isoform 6. Isoform N3 and isoform 12 are phosphorylated on Ser-49, Ser-51, Ser-55 and Ser-59.By similarity
Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation.1 Publication

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ08499.
PaxDbiQ08499.
PeptideAtlasiQ08499.
PRIDEiQ08499.

PTM databases

iPTMnetiQ08499.
PhosphoSitePlusiQ08499.

Expressioni

Tissue specificityi

Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle. Isoform 6 is detected in brain. Isoform 8 is detected in brain, placenta, lung and kidney. Isoform 7 is detected in heart and skeletal muscle.2 Publications

Gene expression databases

BgeeiENSG00000113448.
ExpressionAtlasiQ08499. baseline and differential.
GenevisibleiQ08499. HS.

Organism-specific databases

HPAiHPA045895.

Interactioni

Subunit structurei

Homodimer for the long isoforms. Isoforms with truncated N-termini are monomeric. Isoform 3 is part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9. Interacts with PDE4DIP. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Isoform 5, isoform N3 and isoform 12 bind RACK1 via their unique N-terminus. Binds ARRB2. Interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner.By similarity15 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Adcy2P267693EBI-8095525,EBI-1027877From a different organism.
COILP384323EBI-1642831,EBI-945751
GOLGA8DPQ0D2H93EBI-1642831,EBI-10181276
GOLGA8GQ08AF83EBI-1642831,EBI-10181260
MAGEA6P433603EBI-1642831,EBI-1045155
TRAF1Q130773EBI-1642831,EBI-359224
ZDHHC17Q8IUH52EBI-9090666,EBI-524753

GO - Molecular functioni

  • ATPase binding Source: BHF-UCL
  • beta-2 adrenergic receptor binding Source: BHF-UCL
  • enzyme binding Source: BHF-UCL
  • ion channel binding Source: BHF-UCL
  • scaffold protein binding Source: BHF-UCL
  • ubiquitin protein ligase binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi111170. 46 interactors.
DIPiDIP-29709N.
DIP-41115N.
IntActiQ08499. 24 interactors.
MINTiMINT-92262.
STRINGi9606.ENSP00000345502.

Chemistry databases

BindingDBiQ08499.
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