UniProt functional annotation for Q08499



	UniProt functional annotation for Q08499

UniProt code: Q08499.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036}.

Catalytic activity: Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165, ChEBI:CHEBI:456215; EC=3.1.4.53;

Cofactor: Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240; Evidence={ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036}; Note=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. {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036};

Activity regulation: Inhibited by rolipram. Activated by phosphatidic acid. {ECO:0000269|PubMed:15131123}.

Pathway: Purine metabolism; 3',5'-cyclic AMP degradation; AMP from 3',5'-cyclic AMP: step 1/1.

Subunit: 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. {ECO:0000250, ECO:0000269|PubMed:12193273, ECO:0000269|PubMed:12387865, ECO:0000269|PubMed:12842049, ECO:0000269|PubMed:14500724, ECO:0000269|PubMed:14609333, ECO:0000269|PubMed:14668322, ECO:0000269|PubMed:15003452, ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036, ECO:0000269|PubMed:15685167, ECO:0000269|PubMed:16539372, ECO:0000269|PubMed:17244609, ECO:0000269|PubMed:17582435, ECO:0000269|PubMed:17727341, ECO:0000269|PubMed:17900862}.

Subcellular location: Apical cell membrane {ECO:0000269|PubMed:14500724}. Cytoplasm {ECO:0000250}. Membrane {ECO:0000250}. Cytoplasm, cytoskeleton {ECO:0000250}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250}. Note=Found in the soluble fraction, associated with membranes, and associated with the cytoskeleton and the centrosome (By similarity). Colocalized with SHANK2 to the apical membrane of colonic crypt cells. {ECO:0000250}.

Tissue specificity: 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. {ECO:0000269|PubMed:12834813, ECO:0000269|PubMed:17244609}.

Ptm: 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. {ECO:0000250}.

Ptm: Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation. {ECO:0000269|PubMed:20196770}.

Disease: Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. {ECO:0000269|PubMed:17006457}.

Disease: Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613]: A 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. {ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}. Note=The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous: [Isoform 3]: Activated by phosphorylation at Ser-53. Mutagenesis of Ser-54 abolishes activation. {ECO:0000305}.

Similarity: Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269\|PubMed:15260978, ECO:0000269\|PubMed:15576036}.


Catalytic activity:		Reaction=3',5'-cyclic AMP + H2O = AMP + H(+); Xref=Rhea:RHEA:25277, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:58165, ChEBI:CHEBI:456215; EC=3.1.4.53;
Cofactor:		Name=a divalent metal cation; Xref=ChEBI:CHEBI:60240; Evidence={ECO:0000269\|PubMed:15260978, ECO:0000269\|PubMed:15576036}; Note=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. {ECO:0000269\|PubMed:15260978, ECO:0000269\|PubMed:15576036};
Activity regulation:		Inhibited by rolipram. Activated by phosphatidic acid. {ECO:0000269\|PubMed:15131123}.
Pathway:		Purine metabolism; 3',5'-cyclic AMP degradation; AMP from 3',5'-cyclic AMP: step 1/1.
Subunit:		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. {ECO:0000250, ECO:0000269\|PubMed:12193273, ECO:0000269\|PubMed:12387865, ECO:0000269\|PubMed:12842049, ECO:0000269\|PubMed:14500724, ECO:0000269\|PubMed:14609333, ECO:0000269\|PubMed:14668322, ECO:0000269\|PubMed:15003452, ECO:0000269\|PubMed:15260978, ECO:0000269\|PubMed:15576036, ECO:0000269\|PubMed:15685167, ECO:0000269\|PubMed:16539372, ECO:0000269\|PubMed:17244609, ECO:0000269\|PubMed:17582435, ECO:0000269\|PubMed:17727341, ECO:0000269\|PubMed:17900862}.
Subcellular location:		Apical cell membrane {ECO:0000269\|PubMed:14500724}. Cytoplasm {ECO:0000250}. Membrane {ECO:0000250}. Cytoplasm, cytoskeleton {ECO:0000250}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250}. Note=Found in the soluble fraction, associated with membranes, and associated with the cytoskeleton and the centrosome (By similarity). Colocalized with SHANK2 to the apical membrane of colonic crypt cells. {ECO:0000250}.
Tissue specificity:		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. {ECO:0000269\|PubMed:12834813, ECO:0000269\|PubMed:17244609}.
Ptm:		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. {ECO:0000250}.
Ptm:		Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation. {ECO:0000269\|PubMed:20196770}.
Disease:		Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. {ECO:0000269\|PubMed:17006457}.
Disease:		Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613]: A 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. {ECO:0000269\|PubMed:22464250, ECO:0000269\|PubMed:22464252, ECO:0000269\|PubMed:23033274, ECO:0000269\|PubMed:23043190}. Note=The disease is caused by variants affecting the gene represented in this entry.
Miscellaneous:		[Isoform 3]: Activated by phosphorylation at Ser-53. Mutagenesis of Ser-54 abolishes activation. {ECO:0000305}.
Similarity:		Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily. {ECO:0000305}.