P27791 (KAPCA_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 135. History...
Names and origin
|Protein names||Recommended name:|
cAMP-dependent protein kinase catalytic subunit alpha
Short name=PKA C-alpha
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||351 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Phosphorylates a large number of substrates in the cytoplasm and the nucleus. 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. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. 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 VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca2+, leading to reduced amplitude and increased frequency of store overload-induced Ca2+ release (SOICR) characterized by an increased rate of Ca2+ release and propagation velocity of spontaneous Ca2+ waves, despite reduced wave amplitude and resting cytosolic Ca2+. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation By similarity. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation By similarity. Ref.4
ATP + a protein = ADP + a phosphoprotein.
Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis.
A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with NFKB1, NFKB2 and NFKBIA in platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes By similarity. Interacts with APOBEC3G and AICDA By similarity. Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly. Ref.5 Ref.6
Cytoplasm By similarity. Cell membrane By similarity. Nucleus By similarity. Mitochondrion By similarity. Note: Translocates into the nucleus (monomeric catalytic subunit). The inactive holoenzyme is found in the cytoplasm. Distributed throughout the cytoplasm in meiotically incompetent oocytes. Associated to mitochondrion as meiotic competence is acquired. Aggregates around the germinal vesicles (GV) at the immature GV stage oocytes By similarity.
Asn-3 is deaminated to Asp in more than 25% of the proteins, giving rise to 2 major isoelectric variants, called CB and CA respectively (0.4 pH unit change). Deamidation proceeds via the so-called beta-aspartyl shift mechanism and yields either 'D-Asp-2' (major) or 'D-isoAsp-2' (minor), in addition to L-isomers. Deamidation occurs after the addition of myristate. The Asn-3 form reaches a significantly larger nuclear/cytoplasmic ratio than the 'Asp-2' form.
Autophosphorylated. Phosphorylation is enhanced by vitamin K2. Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity By similarity. Ref.6
Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficienncy By similarity. Ref.6
Contains 1 AGC-kinase C-terminal domain.
Contains 1 protein kinase domain.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: P27791-1) |
Also known as: C-alpha-1;
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.
|Isoform 2 (identifier: P27791-2) |
Also known as: Cs;
The sequence of this isoform differs from the canonical sequence as follows:
2-15: GNAAAAKKGSEQES → MASNSND
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 351||350||cAMP-dependent protein kinase catalytic subunit alpha||PRO_0000086055|
|Domain||44 – 298||255||Protein kinase|
|Domain||299 – 351||53||AGC-kinase C-terminal|
|Nucleotide binding||50 – 58||9||ATP By similarity|
|Nucleotide binding||122 – 128||7||ATP By similarity|
|Nucleotide binding||169 – 172||4||ATP By similarity|
|Active site||167||1||Proton acceptor By similarity|
|Binding site||73||1||ATP By similarity|
Amino acid modifications
|Modified residue||3||1||Deamidated asparagine; partial Ref.2|
|Modified residue||11||1||Phosphoserine; by autocatalysis By similarity|
|Modified residue||49||1||Phosphothreonine By similarity|
|Modified residue||140||1||Phosphoserine Ref.6|
|Modified residue||196||1||Phosphothreonine By similarity|
|Modified residue||198||1||Phosphothreonine; by PDPK1 Ref.6|
|Modified residue||202||1||Phosphothreonine By similarity|
|Modified residue||331||1||Phosphotyrosine By similarity|
|Modified residue||339||1||Phosphoserine By similarity|
|Lipidation||2||1||N-myristoyl glycine Ref.2|
|Alternative sequence||2 – 15||14||GNAAA…SEQES → MASNSND in isoform 2.||VSP_013277|
Helix Strand Turn
|Helix||21 – 32||12|
|Helix||41 – 43||3|
|Beta strand||44 – 49||6|
|Beta strand||59 – 63||5|
|Turn||64 – 66||3|
|Beta strand||69 – 76||8|
|Helix||77 – 82||6|
|Helix||86 – 97||12|
|Beta strand||107 – 112||6|
|Beta strand||114 – 122||9|
|Helix||129 – 136||8|
|Helix||141 – 160||20|
|Helix||170 – 172||3|
|Beta strand||173 – 175||3|
|Beta strand||181 – 183||3|
|Helix||203 – 205||3|
|Helix||208 – 211||4|
|Helix||219 – 234||16|
|Helix||244 – 253||10|
|Helix||264 – 273||10|
|Turn||278 – 280||3|
|Turn||286 – 289||4|
|Helix||290 – 293||4|
|Helix||296 – 298||3|
|Helix||303 – 308||6|
|Turn||345 – 350||6|
|||"Rat C alpha catalytic subunit of the cAMP-dependent protein kinase: cDNA sequence and evidence that it is the only isoform expressed in myoblasts."|
Wiemann S., Voss H., Kinzel V., Pyerin W.
Biochim. Biophys. Acta 1089:254-256(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
|||"A conserved deamidation site at Asn 2 in the catalytic subunit of mammalian cAMP-dependent protein kinase detected by capillary LC-MS and tandem mass spectrometry."|
Jedrzejewski P.T., Girod A., Tholey A., Koenig N., Thullner S., Kinzel V., Bossemeyer D.
Protein Sci. 7:457-469(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 2-8 (ISOFORM 1), MYRISTOYLATION AT GLY-2, DEAMIDATION AT ASN-3.
|||"Phosphorylation of rat spermatidal protein TP2 by sperm-specific protein kinase A and modulation of its transport into the haploid nucleus."|
Ullas K.S., Rao M.R.S.
J. Biol. Chem. 278:52673-52680(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-313 (ISOFORM 2), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE.
|||"Protein kinase A in the pedunculopontine tegmental nucleus of rat contributes to regulation of rapid eye movement sleep."|
Datta S., Desarnaud F.
J. Neurosci. 30:12263-12273(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN RAPID EYE MOVEMENT SLEEP.
|||"RAB13 regulates Sertoli cell permeability barrier dynamics through protein kinase A."|
Su W., Liu X.
J. Mol. Endocrinol. 50:305-318(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RAB13.
|||"Structure and allostery of the PKA RIIbeta tetrameric holoenzyme."|
Zhang P., Smith-Nguyen E.V., Keshwani M.M., Deal M.S., Kornev A.P., Taylor S.S.
Science 335:712-716(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 2-351 IN COMPLEX WITH MOUSE PRKAR2B, SUBUNIT, PHOSPHORYLATION AT SER-140 AND THR-198.
|+||Additional computationally mapped references.|
|X57986 mRNA. Translation: CAA41052.1.|
AY375243 mRNA. Translation: AAQ81631.1.
|PIR||OKRT2C. S16240. |
3D structure databases
|SMR||P27791. Positions 13-351. |
Protein-protein interaction databases
|IntAct||P27791. 3 interactions.|
Protocols and materials databases
|RGD||3389. Prkaca. |
Enzyme and pathway databases
|BRENDA||22.214.171.124. 5301. |
Gene expression databases
Family and domain databases
|InterPro||IPR000961. AGC-kinase_C. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00133. S_TK_X. 1 hit. |
SM00220. S_TKc. 1 hit.
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS51285. AGC_KINASE_CTER. 1 hit. |
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: P27791|
Secondary accession number(s): Q6UA68
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|