Any feedback?
Information on EC 2.7.11.11 - cAMP-dependent protein kinase and Organism(s) Mus musculus and UniProt Accession P68181
for references in articles please use BRENDA:EC2.7.11.11Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
2.7.11.11 cAMP-dependent protein kinaseIUBMB Comments
This eukaryotic enzyme recognizes the sequence -Arg-Arg-X-Ser*/Thr*-Hpo, where * indicates the phosphorylated residue and Hpo indicates a hydrophobic residue.The inactive holoenzyme is a heterotetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. Each R subunit occludes the active site of a C subunit and contains two binding sites for 3',5'-cyclic-AMP (cAMP). Binding of cAMP activates the enzyme by causing conformational changes that release two free monomeric C subunits from a dimer of the R subunits, i.e. R2C2 + 4 cAMP = R2(cAMP)4 + 2 C. Activity requires phosphorylation of a conserved Thr in the activation loop (T-loop) sequence (Thr198 in human Calpha; Thr224 in budding yeast Tpk2), installed by auto-phosphorylation or by the 3-phosphoinositide-dependent protein kinase-1 (PDPK1). Certain R2C2 combinations can be localized to particular subcellular regions by their association with diverse species of 'A Kinase-Anchoring Proteins' (AKAPs). The enzyme has been characterized from many organisms. Humans have three C units (Calpha, Cbeta, and Cgamma) encoded by the paralogous genes PRKACA, PRKACB and PRKACG, respectively, and four R subunits (R1alpha, RIbeta, RIIalpha and RIIbeta), encoded by PKRAR1A, PKRAR1B, PKRAR2A and PKRAR2B, respectively. Yeast (Saccharomyces cerevisiae) has three C subunits (Tpk1, Tpk2, and Tpk3) encoded by the paralogous genes TPK1, TPK2 and TPK3, respectively, and a single R subunit (Bcy1) encoded by the BCY1 gene. Some validated substrates of the enzyme include cAMP-response element-binding protein (CREB), phosphorylase kinase alpha subunit (PHKA), and tyrosine 3-monooxygenase (TH) in mammals; Adr1, Whi3, Nej1, and Pyk1 in yeast.
Specify your search results
Word Map
- 2.7.11.11
- cyclase
- forskolin
- agonist
- adenylate
- phosphodiesterase
- cardiac
-
adenylyl
- phosphoprotein
- isoproterenol
- synaptic
-
holoenzyme
- cgmp
-
phorbol
-
dibutyryl
- a-kinase
- prostaglandin
- calmodulin
-
cgmp-dependent
-
beta-adrenergic
- creb
- phosphopeptide
-
desensitization
-
akaps
- autophosphorylation
-
camp-mediated
-
gamma-32patp
- pki
- rp-camps
-
pka-dependent
-
camp-responsive
-
sarcoplasmic
-
l-type
- phospholamban
-
8-br-camp
- 8-bromo-camp
-
calmodulin-dependent
-
pka-mediated
-
camp-independent
-
patch-clamp
- 3',5'-monophosphate
- ibmx
-
camp-induced
- 3-isobutyl-1-methylxanthine
- isoprenaline
-
camp-regulated
-
camp-stimulated
- dibutyryl-camp
-
phosphorylatable
- rolipram
-
phospholipid-dependent
- medicine
- drug development
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Reaction Schemes
+
a [protein]-(L-serine/L-threonine)
=
+
a [protein]-(L-serine/L-threonine) phosphate
Synonyms
camp-dependent protein kinase, a kinase, cyclic amp-dependent protein kinase, camp-pka, camp/protein kinase a, capk, prkaca, camp dependent protein kinase, camp-dependent pka, cyclic amp-dependent protein kinase a, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
cAMP-dependent protein kinase, beta-catalytic subunit
-
A kinase
-
-
-
-
ATP:protein phosphotransferase (cAMP-dependent)
-
-
-
-
cAMP-dependent protein kinase
cAMP-dependent protein kinase A
PK-25
-
-
-
-
PKA
PKA C-alpha
-
-
-
-
PKA C-beta
-
-
-
-
PKA C-gamma
-
-
-
-
PKA Calpha
PKA catalytic (C) subunit
-
-
-
-
PKAc
protein kinase A
cAMP-dependent protein kinase
-
-
-
-
PKA
-
-
-
-
PKA
-
-
protein kinase A
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + a [protein]-(L-serine/L-threonine) = ADP + a [protein]-(L-serine/L-threonine) phosphate
ATP + a [protein]-(L-serine/L-threonine) = ADP + a [protein]-(L-serine/L-threonine) phosphate
active site residues and structure, mechanism of ligand binding and ligand-induced conformational changes
-
ATP + a [protein]-(L-serine/L-threonine) = ADP + a [protein]-(L-serine/L-threonine) phosphate
catalytic mechanism, active site structure, Tyr204 is required and involved in the hydrophobic network, substrate-induced interaction of Tyr204 and Asp166, overview
ATP + a [protein]-(L-serine/L-threonine) = ADP + a [protein]-(L-serine/L-threonine) phosphate
substrate binding site structure involving E230, the electrostatic surface is important for substrate binding and catalysis, and also for the mechanism of closing the active site cleft of subunit C, conformation and mechanism, overview, the catalytic loop consists of residues Arg165-Asn171
ATP + a [protein]-(L-serine/L-threonine) = ADP + a [protein]-(L-serine/L-threonine) phosphate
phosphoryltransfer mechanism, substrate-binding site structure, the phosphorylated Thr197 in the catalytic subunit of cAMP-dependent protein is essential for activity, overview
-
SYSTEMATIC NAME
IUBMB Comments
ATP:protein Ser/Thr-phosphotransferase (3',5'-cAMP-dependent)
This eukaryotic enzyme recognizes the sequence -Arg-Arg-X-Ser*/Thr*-Hpo, where * indicates the phosphorylated residue and Hpo indicates a hydrophobic residue.The inactive holoenzyme is a heterotetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. Each R subunit occludes the active site of a C subunit and contains two binding sites for 3',5'-cyclic-AMP (cAMP). Binding of cAMP activates the enzyme by causing conformational changes that release two free monomeric C subunits from a dimer of the R subunits, i.e. R2C2 + 4 cAMP = R2(cAMP)4 + 2 C. Activity requires phosphorylation of a conserved Thr in the activation loop (T-loop) sequence (Thr198 in human Calpha; Thr224 in budding yeast Tpk2), installed by auto-phosphorylation or by the 3-phosphoinositide-dependent protein kinase-1 (PDPK1). Certain R2C2 combinations can be localized to particular subcellular regions by their association with diverse species of 'A Kinase-Anchoring Proteins' (AKAPs). The enzyme has been characterized from many organisms. Humans have three C units (Calpha, Cbeta, and Cgamma) encoded by the paralogous genes PRKACA, PRKACB and PRKACG, respectively, and four R subunits (R1alpha, RIbeta, RIIalpha and RIIbeta), encoded by PKRAR1A, PKRAR1B, PKRAR2A and PKRAR2B, respectively. Yeast (Saccharomyces cerevisiae) has three C subunits (Tpk1, Tpk2, and Tpk3) encoded by the paralogous genes TPK1, TPK2 and TPK3, respectively, and a single R subunit (Bcy1) encoded by the BCY1 gene. Some validated substrates of the enzyme include cAMP-response element-binding protein (CREB), phosphorylase kinase alpha subunit (PHKA), and tyrosine 3-monooxygenase (TH) in mammals; Adr1, Whi3, Nej1, and Pyk1 in yeast.
CAS REGISTRY NUMBER
COMMENTARY
142008-29-5
-
142008-29-5
cAMP-dependent protein kinase
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + cAMP-responsive element binding protein
ADP + phosphorylated cAMP-responsive element binding protein
ATP + cAMP-responsive element-binding protein
ADP + phosphorylated cAMP-responsive element-binding protein
-
-
-
-
?
ATP + ChChd3
ADP + phosphorylated ChChd3
-
an endogenous mitochondrial protein
-
-
?
ATP + CRE-binding protein
ADP + CRE-binding phosphoprotein
-
i.e. CREB, a transcription factor, activition by type I PKA
-
-
?
ATP + CREB-binding protein
ADP + CREB-binding phosphoprotein
-
i.e. CBP, activition by type II PKA
-
-
?
ATP + histone IIIS
ADP + phosphorylated histone IIIS
-
activity of the catalytic subunit Cgamma
-
-
?
ATP + Kemptide
ADP + phosphorylated Kemptide
-
LRRASLG peptides substrate
LRRA-phosphoserine-LG
-
?
ATP + Leu-Arg-Arg-Ala-Ser-Leu-Gly
ADP + Leu-Arg-Arg-Ala-phospho-Ser-Leu-Gly
-
commercial artificial heptapeptide substrate kemptide
-
-
?
ATP + myocyte enhancer factor 2D
ADP + phosphorylated myocyte enhancer factor 2D
-
myocyte enhancer factor 2D serine 121 and serine 190 are targeted by PKA
-
-
?
ATP + NDUFS4 subunit of complex I
ADP + phosphorylated NDUFS4 subunit of complex I
-
complex I is the NADH-ubiquinone oxidoreductase, E.C 1.6.5.3
-
-
?
ATP + phosphofructokinase 2
ADP + phosphorylated phosphofructokinase 2
-
-
-
-
?
ATP + RFARKGSLREKNV
ADP + RFARKG-phosphoserine-LREKNV
-
protein kinase C-derived peptide, activity of the catalytic subunit Calpha
-
-
?
ATP + RKRSRAE
ADP + RKR-phosphoserine-RAE
-
cGPK-1-derived peptide, activity of the catalytic subunit Calpha
-
-
?
ATP + RKRSRKE
ADP + RKR-phosphoserine-RKE
-
cGPK-2-derived peptide, activity of the catalytic subunit Calpha
-
-
?
ATP + RRLSSLRA
ADP + RRL-phosphoserine-phosphoserine-LRA
-
S6 kinase-derived peptide, activity of the catalytic subunit Calpha
-
-
?
ATP + SP20
ADP + SP20 phosphate
-
substrate peptide, the C subunit SP20-binding residues are E203, F129, E170, E230, D166, and K168
-
-
?
ATP + SP20 protein
ADP + phosphorylated SP20 protein
i.e. TTYADFIASGRTGRRASIHD
-
-
?
N6-benzyl-ATP + ChChd3
N6-benzyl-ADP + phosphorylated ChChd3
-
cofactor of mutant M120G, poor activity with the wild-type catalytic subunit
-
-
?
N6-phenethyl-ATP + ChChd3
N6-phenethyl-ADP + phosphorylated ChChd3
-
cofactor of mutant M120G, poor activity with the wild-type catalytic subunit
-
-
?
ATP + cAMP-responsive element binding protein
ADP + phosphorylated cAMP-responsive element binding protein
-
i.e. CREB
-
-
?
ATP + cAMP-responsive element binding protein
ADP + phosphorylated cAMP-responsive element binding protein
-
the enzyme as well as GABAB receptors are involved in induction of cAMP-responsive element binding protein phosphorylation in hippocampus by gamma-hydroxybutyrate, overview
-
-
?
ATP + Kemptide
ADP + Kemptide phosphate
-
activity of the catalytic subunit Calpha
-
-
?
additional information
?
-
-
oestrogen-dependent increase in cAMP increases Ca2+-dependent exocytosis through protein kinase A-dependent pathway and through alternative cAMP-guanine nucleotide exchange factor GEF/Epac-dependent pathway in secretory cells
-
-
?
additional information
?
-
-
PKA type I regulates ethanol-induced cAMP response element-mediated gene expression via activation of CREB-binding protein and inhibition of MAPK, regulation overview
-
-
?
additional information
?
-
-
the enzyme autophosphorylates at Ser10, Thr197, and Ser338 of PKA Calpha, substrate-induced conformational changes
-
-
?
additional information
?
-
-
the enzyme performs autophosphorylation at K72, S338, and T197
-
-
?
additional information
?
-
-
the enzyme is involved in cyclic nucleotide signaling, overview, individually phosphorylated PKA-R isozymes are differentially targeted to distinct cellular compartments by AKAP-isozymes, providing a multifaceted platform for the kinase
-
-
?
additional information
?
-
the catalytic subunit has a cluster of nonconserved acidic residues, Glu127, Glu170, Glu203, Glu230, and Asp241, that are crucial for substrate recognition and binding
-
-
?
additional information
?
-
-
signaling by cAMP-dependent protein kinase plays an important role in the regulation of mammalian sperm motility
-
-
?
additional information
?
-
-
localized PKA activity is required for fusion of mononucleated myoblasts and plays a pivotal role in the early steps of myogenic cell fusion
-
-
?
additional information
?
-
-
the activation of protein kinase A is required for TIP39-mediated nociception
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + cAMP-responsive element binding protein
ADP + phosphorylated cAMP-responsive element binding protein
-
the enzyme as well as GABAB receptors are involved in induction of cAMP-responsive element binding protein phosphorylation in hippocampus by gamma-hydroxybutyrate, overview
-
-
?
ATP + CRE-binding protein
ADP + CRE-binding phosphoprotein
-
i.e. CREB, a transcription factor, activition by type I PKA
-
-
?
ATP + CREB-binding protein
ADP + CREB-binding phosphoprotein
-
i.e. CBP, activition by type II PKA
-
-
?
ATP + NDUFS4 subunit of complex I
ADP + phosphorylated NDUFS4 subunit of complex I
-
complex I is the NADH-ubiquinone oxidoreductase, E.C 1.6.5.3
-
-
?
ATP + phosphofructokinase 2
ADP + phosphorylated phosphofructokinase 2
-
-
-
-
?
additional information
?
-
-
oestrogen-dependent increase in cAMP increases Ca2+-dependent exocytosis through protein kinase A-dependent pathway and through alternative cAMP-guanine nucleotide exchange factor GEF/Epac-dependent pathway in secretory cells
-
-
?
additional information
?
-
-
PKA type I regulates ethanol-induced cAMP response element-mediated gene expression via activation of CREB-binding protein and inhibition of MAPK, regulation overview
-
-
?
additional information
?
-
-
the enzyme is involved in cyclic nucleotide signaling, overview, individually phosphorylated PKA-R isozymes are differentially targeted to distinct cellular compartments by AKAP-isozymes, providing a multifaceted platform for the kinase
-
-
?
additional information
?
-
-
signaling by cAMP-dependent protein kinase plays an important role in the regulation of mammalian sperm motility
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
N6-benzyl-ATP
-
preferred co-substrate of catalytic subunit mutant M120G, but inhibitory versus kemptide, overview
N6-phenethyl-ATP
-
preferred co-substrate of catalytic subunit mutant M120G, but inhibitory versus kemptide, overview
ATP
-
-
662279, 662452, 662709, 663295, 663394, 675671, 676192, 677184, 690353, 692216, 694153, 694155, 694279, 721701, 722989
ATP
binding pocket and small lobe structure, binding involves D166, N171, D184, and K72
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
bicarbonate
-
p270 phosphorylation is not observed when sperms are incubated with M2 medium that contains 4.2 mM bicarbonate
N6-benzyl-ATP
-
preferred co-substrate of catalytic subunit mutant M120G, but inhibitory for the mutant, not the wild-type enzyme, versus kemptide, overview
N6-phenethyl-ATP
-
preferred co-substrate of catalytic subunit mutant M120G, but inhibitory for the mutant, not the wild-type enzyme, versus kemptide, overview
pseudosubstrate peptides
-
IC50 values for inhibition of he regulatory subunits of PKA by endogenous inhibitors, overview
-
rhodamine B-PKI(14-22)-GFMK
potent, competitive, irreversible inhibitor, 97% inhibition at 0.001 mM
additional information
-
molecular mechanism of enzyme inhibition by binding of catalytic and regulatory subunits via extended surface of subunit C, overview
-
H-89
-
i.e. N-[2-((4-bromocinnamyl)amino)ethyl]5-isoquinolinesulfonamide, as hydrochloride
IP20
inhibitory peptide TTYADFIASGRTGRRN, residues 5-24 of inhibitor PKI, inhibits the ATPase function of the enzyme
IP20
-
peptide RRNAI, derived from the inhibitory sequence of RIalpha comprising residues 94-98, inhibition mechanism
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
transforming growth factor beta
-
more than 2fold increased activity after 15 min at 0.1 nM
-
cAMP
-
dependent on, structural basis of activation mechanism, binding induces conformational changes in the regulatory subunit RIalpha
forskolin
-
0.024 mM, forskolin enhances lamellipodium formation where active PKA is accumulated
additional information
-
phosphorylation of CBP by PKA type I is induced by forskolin and ethanol, inhibition of MAPK activates the PKA type I
-
additional information
-
PKA is induced by oestrogen 17beta-oestradiol and forskolin
-
additional information
-
gamma-hydroxybutyrate induces the enzyme in the hippocampus, the phosphorylation activity is increased via GABAB receptors, but a desensitization of the signaling pathway occurs after repeated administration of gamma-hydroxybutyrate, overview
-
additional information
-
not activated by 8-(4-chlorophenylthio)-2'-O-methyl-cAMP
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0015
N6-phenethyl-ATP
-
pH 7.0, 37°C, recombinant mutant M120G catalytic subunit
additional information
additional information
-
kinetics for catalytic subunit Cgamma
-
0.019
ATP
-
pH 7.0, temperature not specified in the publication, wild-type enzyme
0.023
ATP
-
pH 7.0, temperature not specified in the publication, myristoylated wild-type enzyme and enzyme mutant K7C
0.032
ATP
-
pH 7.0, temperature not specified in the publication, myristoylated enzyme mutant K7C
0.023
Leu-Arg-Arg-Ala-Ser-Leu-Gly
-
pH 7.0, temperature not specified in the publication, myristoylated wild-type enzyme
0.027
Leu-Arg-Arg-Ala-Ser-Leu-Gly
-
pH 7.0, temperature not specified in the publication, enzyme mutant K7C
0.029
Leu-Arg-Arg-Ala-Ser-Leu-Gly
-
pH 7.0, temperature not specified in the publication, wild-type enzyme
0.043
Leu-Arg-Arg-Ala-Ser-Leu-Gly
-
pH 7.0, temperature not specified in the publication, myristoylated enzyme mutant K7C
0.1
N6-benzyl-ATP
-
above, pH 7.0, 37°C, recombinant wild-type catalytic subunit
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.12
N6-phenethyl-ATP
-
pH 7.0, 37°C, recombinant mutant M120G catalytic subunit
18
Leu-Arg-Arg-Ala-Ser-Leu-Gly
-
pH 7.0, temperature not specified in the publication, myristoylated wild-type enzyme and enzyme mutant K7C
19
Leu-Arg-Arg-Ala-Ser-Leu-Gly
-
pH 7.0, temperature not specified in the publication, wild-type enzyme
29
Leu-Arg-Arg-Ala-Ser-Leu-Gly
-
pH 7.0, temperature not specified in the publication, myristoylated enzyme mutant K7C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000479
myr-PKI(14-22)
Mus musculus
pH and temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
C alpha mRNA is widespread and highly expressed in brain, heart, adrenal gland, testis, lung, kidney, spleen and liver, whereas the C beta mRNA is unevenly expressed in the brain and adrenal gland and in much lesser amounts in other tissues
additional information
-
C alpha mRNA is widespread and highly expressed in brain, heart, adrenal gland, testis, lung, kidney, spleen and liver, whereas the C beta mRNA is unevenly expressed in the brain and adrenal gland and in much lesser amounts in other tissues
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
individually phosphorylated PKA-R isozymes are differentially targeted to distinct cellular compartments by AKAP-isozymes
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
exploration and elucidation of the evolution of the alternative 5' exons and the splicing pattern giving rise to the numerous PKA catalytic subunit isoforms. Alignment of the segments encoded by Calpha1- and Cbeta1-specific 5'exons
evolution
exploration and elucidation of the evolution of the alternative 5' exons and the splicing pattern giving rise to the numerous PKA catalytic subunit isoforms. Alignment of the segments encoded by Calpha1- and Cbeta1-specific 5'exons
malfunction
metabolism
physiological function
additional information
-
analysis of proteomic differences between wild-type and enzyme-deficient S-49 cells, overview. Identification of cAMP/PKA-regulated protein expressions
malfunction
-
protein kinase A Calpha and Cbeta ablation both results in a 50% reduction in PKA-specific kinase activity and the level of PKA type I but not PKA type II, PKA subunit Calpha but not Cbeta ablation augments expression of the activation marker CD69 on lymphocytes
malfunction
-
enzyme-deficient cells show a higher glutathione reductase expression level and are less sensitive to cell killing and generation of malondialdehyde than are wild-type cells incubated with H2O2
malfunction
-
enzyme inhibition leads to hypersprouting as a result of an increased number of tip cells
metabolism
-
CREB phosphorylation, by PKA and/or CaMKs, activates at nuclear and mitochondrial level a transcriptional regulatory cascade which promotes the concerted expression of nuclear and mitochondrial encoded subunits of complex I and other respiratory chain proteins. The post-translational cAMP/PKA stimulation of the catalytic activity of complex I, is evidently associated with stimulation of protein biosynthesis, which characterizes the G1 phase of the cell cycle, in which fibroblasts are re-introduced from the G0 phase by serum supplementation
metabolism
-
the catalytic subunit of cAMP-dependent protein kinase is a major target of cAMP signaling, and its regulation is of fundamental importance to biological processes
physiological function
-
protein kinase A Calpha is required for normal immune cell reactivity
physiological function
-
the cAMP-dependent protein kinase, PKA, and the transcription factor CREB play a critical role in the biosynthesis of complex I subunits, and PKA also regulates post-translational processing and expression of complex I subunits in mammalian cells, it promotes the activity of complex I and lowers reactive oxygen species level in mammalian cell cultures, overview. cAMP-dependent phosphorylation of the NDUFS4 subunit of the complex promotes the import in mitochondria of this nuclear encoded protein
physiological function
-
endothelial cAMP-dependent protein kinase A activity is essential for vascular development, specifically regulating the transition from sprouting to stabilization of nascent vessels. The4 enzyme regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). KAPCB_MOUSE
351
0
40708
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
42000
-
1 * 42000, isolated recombinant catalytic subunit Calpha from Escherichia coli, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterotetramer
-
the inactive enzyme is composed of two catalytic and two regulatory subunits
monomer
-
1 * 42000, isolated recombinant catalytic subunit Calpha from Escherichia coli, SDS-PAGE
additional information
additional information
-
apoenzyme structure analysis, hydrophobic core network, overview
additional information
-
determination of Stoke's radius of purified recombinant catalytic subunit Calpha
additional information
-
structure of subunit C, subunit R, the cAMP binding site, and the activation loop, interaction sites, overview
additional information
-
identification of protein kinase A regulatory isoforms and of 11 different A-kinase anchoring proteins, AKAPs, in ventricular tissue, overview
additional information
the catalytic subunit has a cluster of nonconserved acidic residues, Glu127, Glu170, Glu203, Glu230, and Asp241, that are crucial for substrate recognition and binding, protein dynamics of the catalytic C-subunit, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
lipoprotein
-
irreversible covalent N-myristylation of PKA or occupancy of the myristyl binding pocket may serve as a site for allosteric regulation in the catalytic C-subunit. And N-myristylation enhances the thermal stability of the enzyme, the myristylated C-subunit has a higher affinity for membranes alone. PKA cannot be myristylated if Asn2 is mutated to Asp
phosphoprotein
additional information
-
the C-subunit of PKA may be regulated by irreversible deamidation of Asn2. With PKA that is purified from tissues, irreversible deamidation of Asn2 to Asp or isoAsp occurs in about 1/3 of the total C-subunit protein. Also, the deamidated form of the protein has a higher cytosolic-to-nuclear ratio than the non-deamidated protein
phosphoprotein
-
phosphorylation at T197 by exogenous kinase PDK-I, the enzyme performs autophosphorylation at K72, S338 and T197, the latter is phosphorylated first and required for activity, phosphorylation of the other 2 positions take place only if T197 is already phosphorylated, mechanism
phosphoprotein
-
the enzyme autophosphorylates at Ser10, Thr197, and Ser338 of catalytic subunit PKA Calpha
phosphoprotein
the enzyme can be phosphorylated at Thr197, Ser338, Ser10, and Ser139, the phosphorylation status of the enzyme varies, and is chronically reduced in enzyme mutant E230Q
phosphoprotein
-
analysis of in vivo phosphorylation sites on PKA-R reveals the presence of several differentially phosphorylated PKA-R isoforms, using semiquantitative mass spectrometry, overview
phosphoprotein
-
the catalytically active subunit mutant M120G is phosphorylated on Thr197 and Ser338
phosphoprotein
phosphorylation sites of the most abundant PKA C-subunit proteoform are characterized simultaneously using tandem MS methods. Four sites are unambiguously identified as Ser10, Ser11, Ser18, and Ser30 and the remaining phosphorylation sites are localized to Ser2/Ser3, Ser358/Thr368, and Thr[215-224]Tyr in the PKA C-subunit sequence with a 20mer 6xHis-tag added at the N-terminus. Four of these seven phosphorylation sites are located at the 6xHis-tag
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
complex between the catalytic subunit and a deletion mutant regulatory subunit RIalpha comprising residues 91-244, structure determination and analysis
-
crystallization of the muatnt E230Q with MgATP2- and protein kinase inhibitor is only possible as apoenzyme, analysis of the mechanism preventing ternary complex formation by relaxed-complex method
modification and computational analysis of the crystal structure of catalytic subunit in complex with two Mg2+ and a phosphorylated substrate peptide, molecular dynamics simulation overview
-
purified myristylated wild-type PKA and a K7C mutant as binary complex with bound substrate SP20 peptide and as ternary complex with bound substrate SP20 peptide and adenosine-5'-(beta,gamma-imido)triphosphate, hanging drop vapor diffusion method, 8-10 mg/ml protein in 50 mM N,N-bis(2-hydroxyethyl)glycine, 150 mM ammonium acetate, and 10 mM DTT, pH 8.0, is combined in 1:10:20:5 molar ratio of protein:AMP-PNP:Mg2+:SP20 for the ternary complex or 1:5 protein:SP20 for the binary complex, screening and method optimization, mixing of equal volumes of protein and well solution, the latter containing 2-18% 2-methyl-2,4-pentanediol, and mother liquor or buffers ranging from pH 5.35 to pH 8.5, 100 mM 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl) propane-1,3-diol, pH 6.5, and 9% MeOH, 8-10 weeks, 4°C, X-ray diffraction structure determination and analysis at 1.35-2.0 A resolution, modeling
-
purified recombinant catalytic apo-subunit apo-PKA Calpha phosphorylated at Ser10, Thr197, and Ser338, hanging drop vapour diffusion method, 4°C, 0.02 ml of 7.5 mg/ml protein in solution 0.1 mM bicine buffer, pH 8.0, 150 mM ammonium acetate, 10 mM 2-mercaptoethanol, and 3% 2-methyl-2,4-pentanediol versus 1 ml reservoir solution containing 0.1 mM Tris-HCl, pH 7.5, and 10-20% v/v 2-methyl-2,4-pentanediol, temperature-sensitive crystals need 6 months to 1 year to grow, cryoprotection by a gradient of 2-methyl-2,4-pentanediol, X-ray diffraction structure determination and analysis at 2.9 A resolution, molecular replacement
-
purified recombinant catalytic subunit C mutant E230Q in ternary complex with ATP, Mg2+, and IP20, hanging drop vapour diffusion method, protein solution versus reservoir solution containing 0.1 M bicine, pH 8.0, 13% 2-methyl-2,4-pentanediol, and 11% methanol, 4°C, cryoprotection by 15% glycerol, X-ray diffraction structure determination and analysis at 2.8 A resolution
purified recombinant wild-type and mutant PKA catalytic subunits, 0.002 ml 5 mg/ml protein in 50 mM bicine, pH 8.0, 200 mM ammonium acetate, 2 mM DTT, MgCl2, ATP, and IP20, is mixed with 0.001 ml well solution containing 8-12% v/v 2-methyl-2,4-pentanediol and 10 mM DTT, addition of 7% v/v methanol before sealing, X-ray diffraction structure determination and analysis at 1.26 A resolution, modeling
ternary and binary complexes with no metals, Na+ or K+, ATP (orATP-gammaS), and SP20 protein, sitting drop vapor diffusion method, using 100 mM MES-NH4OH, pH 6.5, 5 mM dithiothreitol, 15-20% (w/v) PEG 4000
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E230Q
K7C
-
site-directed mutagenesis, the mutant exhibits altered kinetics in a myristylated state compared to the wild-type enzyme
M120G
-
site-directed mutagenesis in the ATP-binding pocket of the catalytic subunit, engineering of the PKA catalytic subunit to accept bulky N6-substituted ATP analogs, using a chemical genetics approach initially pioneered with v-Src, overview, N6(benzyl)-ATP and N6(phenethyl)-ATP are the prefrred cofactors of the mutant
S338A
-
site-directed mutagenesis, mutant is phosphorylated at T197, reduced activity compared to the wild-type enzyme
T197A
-
site-directed mutagenesis, mutant is not phosphorylated, inactive mutant
Y204A
E230Q
site-directed mutagenesis, mutation of an acidic residue from the cluster around the active site of the catalytic subunit C, E230 forms the salt bridge required for interaction with the substrate, mutant shows decreased substrate recognition, phosphorylation degree, and activity compared to the wild-type subunit C, mutant has an open conformation and does not bind ligands like MgATP2- or IP20 inhibitor
E230Q
site-directed mutagenesis of the catalytic subunit, the mutation affects the local structure of the the F-to-G helix loop and asp241, and the binding of protein kinase inhibitor PKI, the mutant protein can only be crystallizes as apoenzyme
Y204A
site-directed mutagenesis, mutation in the catalytic subunit, reduced catalytic efficiency compared to the wild-type enzyme
Y204A
the mutation desynchronizes the opening and closing of the active cleft without changing the enzyme's structure, rendering it catalytically inefficient
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant catalytic subunit Calpha from Escherichia coli by nickel affinity chromatography, recombinant catalytic subunit Calpha from Sf9 insect cells 62fold by adsorption chromatography and gel filtration
-
recombinant catalytic subunit PKA Calpha from Escherichia coli strain BL21 by P11 cellulose and ion exchange chromatography
-
recombinant His-tagged mutant catalytic subunit M120G from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
-
recombinant wild-type and mutant Y204A from Escherichia coli by ion exchange chromatography and gel filtration
the recombinant PKA C-subunit is purified via His-tag affinity purification
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
characterization of genomic clones coding for the Calpha and Cbeta subunits
isolation of a full-length cDNA clone encoding the C beta catalytic subunit of cAMP-dependent protein kinase from a brain cDNA library
expressed in Escherichia coli
expression of His-tagged catalytic subunit Calpha in Escherichia coli strain BL21(DE3), expression of catalytic subunit Calpha in Spodoptera frugiperda Sf9 cells via baculovirus infection system
-
expression of PKA catalytic subunit Calpha as His-tagged protein in Escherichia coli strain BL21(DE3) and of HA-tagged wild-type and mutant PKA Calpha in COS cells
-
functional expression of His-tagged mutant catalytic subunit M120G in Escherichia coli strain BL21(DE3) requiring co-expression with PDK1 for stabilization, overview
-
recombinant expression of paralemmin 2-AKAP2 fusion protein in ventricular tissue
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
activation of protein kinase A by elevation of the intracellular cAMP level inhibits skeletal myogenesis
medicine
-
cAMP-dependent protein kinase acts synergistically with exchange protein directly activated by cAMP to promote adipogenesis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Boeckmann, B.; Bairoch, A.; Apweiler, R.; Blatter, M.C.; Estreicher, A.; Gasteiger, E.; Martin M.J.; Michoud, K.; O'Donovan, C.; Phan, I.; Pilbout, S.; Schneider, M.
The SWISS-PROT protein knowledgebase and its supplement TrEMBL
Nucleic Acids Res.
31
365-370
2003
Mus musculus (P05132)
Chrivia, J.C.; Uhler, M.D.; McKnight, G.S.
Characterization of genomic clones coding for the C alpha and C beta subunits of mouse cAMP-dependent protein kinase
J. Biol. Chem.
263
5739-5744
1988
Mus musculus (P68181), Mus musculus
Howard, P.; Day, K.H.; Kim, K.E.; Richardson, J.; Thomas, J.; Abraham, I.; Fleischmann, R.D.; Gottesman, M.M.; Maurer, R.A.
Decreased catalytic subunit mRNA levels and altered catalytic subunit mRNA structure in a cAMP-resistant Chinese hamster ovary cell line
J. Biol. Chem.
266
10189-10195
1991
Cricetulus griseus (P25321), Cricetulus griseus (P68180), Cricetulus griseus, Mus musculus (P68181)
Shuntoh, H.; Sakamoto, N.; Matsuyama, S.; Saitoh, M.; Tanaka, C.
Molecular structure of the C beta catalytic subunit of rat cAMP-dependent protein kinase and differential expression of C alpha and C beta isoforms in rat tissues and cultured cells
Biochim. Biophys. Acta
1131
175-180
1992
Mus musculus (P68181), Mus musculus
Uhler, M.D.; Chrivia, J.C.; McKnight, G.S.
Evidence for a second isoform of the catalytic subunit of cAMP-dependent protein kinase
J. Biol. Chem.
261
15360-15363
1986
Mus musculus (P68181), Mus musculus
Constantinescu, A.; Wu, M.; Asher, O.; Diamond, I.
cAMP-dependent protein kinase type I regulates ethanol-induced cAMP response element-mediated gene expression via activation of CREB-binding protein and inhibition of MAPK
J. Biol. Chem.
279
43321-43329
2004
Mus musculus
Iyer, G.H.; Moore, M.J.; Taylor, S.S.
Consequences of lysine 72 mutation on the phosphorylation and activation state of cAMP-dependent kinase
J. Biol. Chem.
280
8800-8807
2005
Mus musculus
Akamine, P.; Madhusudan; Wu, J.; Xuong, N.H.; Ten Eyck, L.F.; Taylor, S.S.
Dynamic features of cAMP-dependent protein kinase revealed by apoenzyme crystal structure
J. Mol. Biol.
327
159-171
2003
Mus musculus
Yang, J.; Ten Eyck, L.F.; Xuong, N.H.; Taylor, S.S.
Crystal structure of a cAMP-dependent protein kinase mutant at 1.26A: new insights into the catalytic mechanism
J. Mol. Biol.
336
473-487
2004
Mus musculus (P05132)
Sedej, S.; Rose, T.; Rupnik, M.
cAMP increases Ca2+-dependent exocytosis through both PKA and Epac2 in mouse melanotrophs from pituitary tissue slices
J. Physiol.
567
799-813
2005
Mus musculus
Zhang, W.; Morris, G.Z.; Beebe, S.J.
Characterization of the cAMP-dependent protein kinase catalytic subunit Cgamma expressed and purified from sf9 cells
Protein Expr. Purif.
35
156-169
2004
Homo sapiens, Mus musculus
Wu, J.; Yang, J.; Kannan, N.; Madhusudan; Xuong, N.H.; Ten Eyck, L.F.; Taylor, S.S.
Crystal structure of the E230Q mutant of cAMP-dependent protein kinase reveals an unexpected apoenzyme conformation and an extended N-terminal A helix
Protein Sci.
14
2871-2879
2005
Mus musculus (P05132)
Kim, C.; Xuong, N.H.; Taylor, S.S.
Crystal structure of a complex between the catalytic and regulatory (RIalpha) subunits of PKA
Science
307
690-696
2005
Mus musculus
Ung, M.; Lu, B.; McCammon, J.A.
E230Q mutation of the catalytic subunit of cAMP-dependent protein kinase affects local structure and the binding of peptide inhibitor
Biopolymers
81
428-439
2006
Mus musculus (P05132)
Schauble, S.; King, C.C.; Darshi, M.; Koller, A.; Shah, K.; Taylor, S.S.
Identification of ChChd3 as a novel substrate of the cAMP-dependent protein kinase (PKA) using an analog-sensitive catalytic subunit
J. Biol. Chem.
282
14952-14959
2007
Mus musculus
Scholten, A.; van Veen, T.A.; Vos, M.A.; Heck, A.J.
Diversity of cAMP-dependent protein kinase isoforms and their anchoring proteins in mouse ventricular tissue
J. Proteome Res.
6
1705-1717
2007
Mus musculus, Mus musculus FVB/N
Ren, X.; Mody, I.
gamma-Hydroxybutyrate induces cyclic AMP-responsive element-binding protein phosphorylation in mouse hippocampus: An involvement of GABAB receptors and cAMP-dependent protein kinase activation
Neuroscience
141
269-275
2006
Mus musculus, Mus musculus C57BL/6
Jin, H.; Wu, T.; Jiang, Y.; Zou, J.; Zhuang, S.; Mao, X.; Yu, Q.
Role of phosphorylated Thr-197 in the catalytic subunit of cAMP-dependent protein kinase
Theochem
805
9-15
2007
Mus musculus
-
Yang, H.; Lee, C.J.; Zhang, L.; Sans, M.D.; Simeone, D.M.
Regulation of transforming growth factor beta-induced responses by protein kinase A in pancreatic acinar cells
Am. J. Physiol. Gastrointest. Liver Physiol.
295
G170-G178
2008
Mus musculus
Mukai, A.; Hashimoto, N.
Localized cyclic AMP-dependent protein kinase activity is required for myogenic cell fusion
Exp. Cell Res.
314
387-397
2008
Mus musculus
Du, M.; Perry, R.L.; Nowacki, N.B.; Gordon, J.W.; Salma, J.; Zhao, J.; Aziz, A.; Chan, J.; Siu, K.W.; McDermott, J.C.
Protein kinase A represses skeletal myogenesis by targeting myocyte enhancer factor 2D
Mol. Cell. Biol.
28
2952-2970
2008
Mus musculus
Petersen, R.K.; Madsen, L.; Pedersen, L.M.; Hallenborg, P.; Hagland, H.; Viste, K.; Doskeland, S.O.; Kristiansen, K.
Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes
Mol. Cell. Biol.
28
3804-3816
2008
Mus musculus
Kaneto, M.; Krisfalusi, M.; Eddy, E.M.; OBrien, D.A.; Miki, K.
Bicarbonate-induced phosphorylation of p270 protein in mouse sperm by cAMP-dependent protein kinase
Mol. Reprod. Dev.
75
1045-1053
2008
Mus musculus
Funderud, A.; Aas-Hanssen, K.; Aksaas, A.K.; Hafte, T.T.; Corthay, A.; Munthe, L.A.; Orstavik, S.; Skalhegg, B.S.
Isoform-specific regulation of immune cell reactivity by the catalytic subunit of protein kinase A (PKA)
Cell. Signal.
21
274-281
2009
Mus musculus
Matsumoto, M.; Kondo, S.; Usdin, T.B.; Ueda, H.
Parathyroid hormone 2 receptor is a functional marker of nociceptive myelinated fibers responsible for neuropathic pain
J. Neurochem.
112
521-530
2010
Mus musculus
Guo, Y.; Wilderman, A.; Zhang, L.; Taylor, S.S.; Insel, P.A.
Quantitative proteomics analysis of the cAMP/protein kinase A signaling pathway
Biochemistry
51
9323-9332
2012
Mus musculus
Papa, S.; Scacco, S.; De Rasmo, D.; Signorile, A.; Papa, F.; Panelli, D.; Nicastro, A.; Scaringi, R.; Santeramo, A.; Roca, E.; Trentadue, R.; Larizza, M.
cAMP-dependent protein kinase regulates post-translational processing and expression of complex I subunits in mammalian cells
Biochim. Biophys. Acta
1797
649-658
2010
Homo sapiens, Mus musculus, Rattus norvegicus, Mus musculus BALB/c
Bastidas, A.C.; Deal, M.S.; Steichen, J.M.; Keshwani, M.M.; Guo, Y.; Taylor, S.S.
Role of N-terminal myristylation in the structure and regulation of cAMP-dependent protein kinase
J. Mol. Biol.
422
215-229
2012
Mus musculus
Gerlits, O.; Das, A.; Keshwani, M.M.; Taylor, S.; Waltman, M.J.; Langan, P.; Heller, W.T.; Kovalevsky, A.
Metal-free cAMP-dependent protein kinase can catalyze phosphoryl transfer
Biochemistry
53
3179-3186
2014
Mus musculus (P05132)
Nedvetsky, P.I.; Zhao, X.; Mathivet, T.; Aspalter, I.M.; Stanchi, F.; Metzger, R.J.; Mostov, K.E.; Gerhardt, H.
cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner
Development
143
3582-3590
2016
Danio rerio, Mus musculus
Bockus, L.B.; Humphries, K.M.
cAMP-dependent protein kinase (PKA) signaling is impaired in the diabetic heart
J. Biol. Chem.
290
29250-29258
2015
Mus musculus
Coover, R.A.; Luzi, N.M.; Korwar, S.; Casile, M.E.; Lyons, C.E.; Peterson, D.L.; Ellis, K.C.
Design, synthesis, and in vitro evaluation of a fluorescently labeled irreversible inhibitor of the catalytic subunit of cAMP-dependent protein kinase (PKACalpha)
Org. Biomol. Chem.
14
4576-4581
2016
Mus musculus (P05132)
Kivi, R.; Loog, M.; Jemth, P.; Jaerv, J.
Kinetics of acrylodan-labelled cAMP-dependent protein kinase catalytic subunit denaturation
Protein J.
32
519-525
2013
Mus musculus
Kivi, R.; Jemth, P.; Jaerv, J.
Thermodynamic aspects of cAMP dependent protein kinase catalytic subunit allostery
Protein J.
33
386-393
2014
Mus musculus
Srivastava, A.K.; McDonald, L.R.; Cembran, A.; Kim, J.; Masterson, L.R.; McClendon, C.L.; Taylor, S.S.; Veglia, G.
Synchronous opening and closing motions are essential for cAMP-dependent protein kinase A signaling
Structure
22
1735-1743
2014
Mus musculus (P05132)
Wu, Z.; Jin, Y.; Chen, B.; Gugger, M.K.; Wilkinson-Johnson, C.L.; Tiambeng, T.N.; Jin, S.; Ge, Y.
Comprehensive characterization of the recombinant catalytic subunit of cAMP-dependent protein kinase by top-down mass spectrometry
J. Am. Soc. Mass Spectrom.
30
2561-2570
2019
Mus musculus (P17612)
Soberg, K.; Moen, L.V.; Skalhegg, B.S.; Laerdahl, J.K.
Evolution of the cAMP-dependent protein kinase (PKA) catalytic subunit isoforms
PLoS ONE
12
e0181091
2017
Alligator mississippiensis, Gallus gallus, Anolis carolinensis, Callorhinchus milii, Aquila chrysaetos, Mus musculus (P05132), Mus musculus (P68181), Homo sapiens (P17612), Homo sapiens (P22694)
EXTERNAL LINKS (specific for EC-Number 2.7.11.11)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
