cAMP-dependent protein kinase catalytic subunit alpha (PRKACA)
The protein contains 351 amino acids for an estimated molecular weight of 40590 Da.
Phosphorylates a large number of substrates in the cytoplasm and the nucleus (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984). Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:15642694, PubMed:15905176, PubMed:16387847, PubMed:17333334, PubMed:17565987, PubMed:17693412, PubMed:18836454, PubMed:19949837, PubMed:20356841, PubMed:21085490, PubMed:21514275, PubMed:21812984). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (PubMed:21423175). RORA is activated by phosphorylation (PubMed:21514275). Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (PubMed:19949837). Involved in chondrogenesis by mediating phosphorylation of SOX9 (By similarity). Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VA (updated: June 17, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.
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| Variant | Description |
|---|---|
| dbSNP:rs56029020 | |
| dbSNP:rs56085217 | |
| PPNAD4 | |
| dbSNP:rs35635531 |
Biological Process
Activation of phospholipase C activity
Activation of protein kinase A activity
Adaptive immune response
Blood coagulation
Calcium-mediated signaling using intracellular calcium source
Carbohydrate metabolic process
Cell communication by electrical coupling involved in cardiac conduction
Cellular response to epinephrine stimulus
Cellular response to glucagon stimulus
Cellular response to glucose stimulus
Cellular response to heat
Cellular response to parathyroid hormone stimulus
Chemical synaptic transmission
Ciliary basal body-plasma membrane docking
Cytokine-mediated signaling pathway
Energy reserve metabolic process
Epidermal growth factor receptor signaling pathway
Fibroblast growth factor receptor signaling pathway
G2/M transition of mitotic cell cycle
Gluconeogenesis
Glucose metabolic process
High-density lipoprotein particle assembly
Innate immune response
Intracellular signal transduction
Mesoderm formation
Mitotic cell cycle
Modulation of chemical synaptic transmission
MRNA processing
Negative regulation of inflammatory response to antigenic stimulus
Negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning
Neural tube closure
Neurotrophin TRK receptor signaling pathway
Organelle organization
Pathogenesis
Peptidyl-serine phosphorylation
Peptidyl-threonine phosphorylation
Positive regulation of cell cycle arrest
Positive regulation of protein export from nucleus
Protein autophosphorylation
Protein kinase A signaling
Protein phosphorylation
Regulation of bicellular tight junction assembly
Regulation of cardiac conduction
Regulation of cardiac muscle contraction
Regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion
Regulation of cytosolic calcium ion concentration
Regulation of G2/M transition of mitotic cell cycle
Regulation of heart rate
Regulation of insulin secretion
Regulation of macroautophagy
Regulation of osteoblast differentiation
Regulation of proteasomal protein catabolic process
Regulation of protein binding
Regulation of protein processing
Regulation of ryanodine-sensitive calcium-release channel activity
Renal water homeostasis
Signal transduction
Small molecule metabolic process
Sperm capacitation
Stimulatory C-type lectin receptor signaling pathway
Transmembrane transport
Triglyceride catabolic process
Water transport
Cellular Component
Acrosomal vesicle
Calcium channel complex
CAMP-dependent protein kinase complex
Centrosome
Ciliary base
Cytoplasm
Cytosol
Dendritic spine
Extracellular exosome
Intercellular bridge
Membrane
Mitochondrion
Motile cilium
Neuromuscular junction
Nuclear speck
Nucleoplasm
Nucleotide-activated protein kinase complex
Nucleus
Obsolete cell
Perinuclear region of cytoplasm
Plasma membrane
Plasma membrane raft
Sperm flagellum
Sperm midpiece
Molecular Function
AMP-activated protein kinase activity
ATP binding
CAMP-dependent protein kinase activity
Magnesium ion binding
Manganese ion binding
Protein domain specific binding
Protein kinase A regulatory subunit binding
Protein kinase activity
Protein kinase binding
Protein serine kinase activity
Protein serine/threonine kinase activity
Protein serine/threonine/tyrosine kinase activity
Protein threonine kinase activity
Ubiquitin protein ligase binding
The reference OMIM entry for this protein is 601639
Protein kinase, camp-dependent, catalytic, alpha; prkaca prkaca/dnajb1 fusion gene, included
DESCRIPTION
Most of the effects of cAMP in the eukaryotic cell are mediated through the phosphorylation of target proteins on serine or threonine residues by the cAMP-dependent protein kinase (EC 2.7.1.37). The inactive cAMP-dependent protein kinase is a tetramer composed of 2 regulatory and 2 catalytic subunits. The cooperative binding of 4 molecules of cAMP dissociates the enzyme in a regulatory subunit dimer and 2 free active catalytic subunits. In the human, 4 different regulatory subunits (PRKAR1A, 188830; PRKAR1B, 176911; PRKAR2A, 176910; and PRKAR2B, 176912) and 3 catalytic subunits (PRKACA; PRKACB, 176892; and PRKACG 176893) have been identified (summary by Tasken et al., 1996).BIOCHEMICAL FEATURES
- Crystal Structure Kim et al. (2005) determined the crystal structure of the cAMP-dependent protein kinase catalytic subunit bound to a deletion mutant of the regulatory subunit (RI-alpha; PRKAR1A, 188830) at 2.0-angstrom resolution. This structure defines a previously unidentified extended interface in which the large lobe of the catalytic subunit is like a stable scaffold where tyr247 in the G helix and trp196 in the phosphorylated activation loop serve as anchor points for binding the RI-alpha subunit. These residues compete with cAMP for the phosphate-binding cassette in RI-alpha. In contrast to this catalytic subunit, RI-alpha undergoes major conformational changes when the complex is compared with cAMP-bound RI-alpha. Kim et al. (2005) concluded that the complex provides a molecular mechanism for inhibition of PKA and suggests how cAMP binding leads to activation. Zhang et al. (2012) described the 2.3-angstrom structure of full-length tetrameric RII-beta (PRKAR2B; 176912)(2):catalytic subunit-alpha(2) holoenzyme. The structure showing a dimer of dimers provided a mechanistic understanding of allosteric activation by cAMP. The heterodimers are anchored together by an interface created by the beta-4/beta-5 loop in the RII-beta subunit, which docks onto the carboxyl-terminal tail of the adjacent C subunit, thereby forcing the C subunit into a fully closed conformation in the absence of nucleotide. Diffusion of magnesium ATP into these crystals trapped not ATP but the reaction products adenosine diphosphate and the phosphorylated RII-beta subunit. This complex has implications for the dissociation-reassociation cycling of PKA. The quaternary structure of the RII-beta tetramer differs appreciably from the model of the RI-alpha tetramer, confirming the small-angle x-ray scattering prediction that the structures of each PKA tetramer are different.MAPPING
Using PCR and Southern blot analysis, Tasken et al. (1996) assigned the PRKACA gene to chromosome 19. By 2-color fluorescence in situ hybridization, they regionalized the assignment to 19p13.1.GENE FUNCTION
Studying hippocampal slices from rats of different ages, Yasuda et al. (2003) found that protein kinase A is required for long-term potentiation (LTP) in neonatal tissue (less than 9 postnatal days). After that time, LTP requires calcium/calmodulin-dependent protein kinase II (see CAMK2A, 114078). Yasuda et al. (2003) suggested that developmental changes in synapse morphology, including a shift from dendritic shafts to dendritic spines and compartmentalization of calcium, may underlie the changes in kinase activity.CYTOGENETICS
Fibrolamellar hepatocellular carcinoma (see HCC, 114550) is a rare liver tumor affecting adolesce ... More on the omim web site
June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 25, 2017: Additional information
No protein expression data in P. Mayeux work for PRKACA
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601639 was added.
Jan. 27, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed