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Protein

cAMP-dependent protein kinase catalytic subunit alpha

Gene

Prkaca

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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). Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (By similarity).By similarity1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

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.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei73ATPPROSITE-ProRule annotation1
Active sitei167Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi50 – 58ATPPROSITE-ProRule annotation9
Nucleotide bindingi122 – 128ATPPROSITE-ProRule annotation7
Nucleotide bindingi169 – 172ATPPROSITE-ProRule annotation4

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • cAMP-dependent protein kinase activity Source: RGD
  • protein complex binding Source: RGD
  • protein kinase A regulatory subunit binding Source: RGD
  • protein kinase binding Source: BHF-UCL
  • protein serine/threonine kinase activity Source: Reactome
  • Rab GTPase binding Source: UniProtKB

GO - Biological processi

  • cellular response to heat Source: UniProtKB
  • gluconeogenesis Source: Reactome
  • intracellular signal transduction Source: Reactome
  • negative regulation of meiotic cell cycle Source: RGD
  • peptidyl-serine phosphorylation Source: RGD
  • positive regulation of cell proliferation Source: RGD
  • protein phosphorylation Source: RGD
  • regulation of cellular respiration Source: RGD
  • regulation of synaptic transmission, glutamatergic Source: RGD
  • triglyceride catabolic process Source: Reactome

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, cAMP, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.11. 5301.
ReactomeiR-RNO-111931. PKA-mediated phosphorylation of CREB.
R-RNO-163358. PKA-mediated phosphorylation of key metabolic factors.
R-RNO-163560. Triglyceride catabolism.
R-RNO-381676. Glucagon-like Peptide-1 (GLP1) regulates insulin secretion.
R-RNO-70263. Gluconeogenesis.

Names & Taxonomyi

Protein namesi
Recommended name:
cAMP-dependent protein kinase catalytic subunit alpha (EC:2.7.11.11)
Short name:
PKA C-alpha
Gene namesi
Name:Prkaca
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi3389. Prkaca.

Subcellular locationi

  • Cytoplasm By similarity
  • Cell membrane By similarity
  • Nucleus By similarity
  • Mitochondrion By similarity
  • Membrane By similarity; Lipid-anchor 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). Colocalizes with HSF1 in nuclear stress bodies (nSBs) upon heat shock (By similarity).By similarity
Isoform 2 :
  • Cell projectionciliumflagellum By similarity
  • Cytoplasmic vesiclesecretory vesicleacrosome By similarity

  • Note: Expressed in the midpiece region of the sperm flagellum. Expressed in the midpiece region of the sperm flagellum. Colocalizes with MROH2B and TCP11 on the acrosome and tail regions in round spermatids and spermatozoa regardless of the capacitation status of the sperm.By similarity

GO - Cellular componenti

  • acrosomal vesicle Source: UniProtKB
  • cAMP-dependent protein kinase complex Source: RGD
  • cytoplasm Source: RGD
  • cytosol Source: Reactome
  • Golgi apparatus Source: RGD
  • membrane Source: RGD
  • mitochondrion Source: UniProtKB-SubCell
  • neuron projection Source: RGD
  • nucleoplasm Source: Reactome
  • nucleus Source: RGD
  • perinuclear region of cytoplasm Source: RGD
  • plasma membrane Source: UniProtKB-SubCell
  • protein complex Source: RGD
  • sperm flagellum Source: UniProtKB
  • sperm midpiece Source: UniProtKB

Keywords - Cellular componenti

Cell membrane, Cell projection, Cilium, Cytoplasm, Cytoplasmic vesicle, Flagellum, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL3390.
GuidetoPHARMACOLOGYi1476.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved1 Publication
ChainiPRO_00000860552 – 351cAMP-dependent protein kinase catalytic subunit alphaAdd BLAST350

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycine1 Publication1
Modified residuei3Deamidated asparagine; partial1 Publication1
Modified residuei11Phosphoserine; by autocatalysisBy similarity1
Modified residuei49PhosphothreonineBy similarity1
Modified residuei140PhosphoserineBy similarity1
Modified residuei196PhosphothreonineBy similarity1
Modified residuei198Phosphothreonine; by PDPK1By similarity1
Modified residuei202PhosphothreonineBy similarity1
Modified residuei331PhosphotyrosineBy similarity1
Modified residuei339PhosphoserineCombined sources1

Post-translational modificationi

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.1 Publication
Autophosphorylated. Phosphorylation is enhanced by vitamin K2. Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity (By similarity).By similarity
Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficienncy.By similarity

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein

Proteomic databases

PaxDbiP27791.
PRIDEiP27791.

PTM databases

iPTMnetiP27791.
PhosphoSitePlusiP27791.

Expressioni

Tissue specificityi

Ubiquitously expressed. Isoform 2 is round spermatid specific.2 Publications

Developmental stagei

In spermatids, isoform 1 is expressed until spermatids become elutriated, whereafter isoform 2 is expressed.1 Publication

Interactioni

Subunit structurei

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. Found in a complex at least composed of MROH2B, PRKACA isoform 2 and TCP11 (By similarity). Interacts with MROH2B (By similarity). Interacts with HSF1 (By similarity). Isoform 2 interacts with TCP11 (By similarity).By similarity1 Publication

GO - Molecular functioni

  • protein complex binding Source: RGD
  • protein kinase A regulatory subunit binding Source: RGD
  • protein kinase binding Source: BHF-UCL
  • Rab GTPase binding Source: UniProtKB

Protein-protein interaction databases

DIPiDIP-37312N.
IntActiP27791. 3 interactors.
MINTiMINT-4564372.
STRINGi10116.ENSRNOP00000044732.

Chemistry databases

BindingDBiP27791.

Structurei

3D structure databases

ProteinModelPortaliP27791.
SMRiP27791.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini44 – 298Protein kinasePROSITE-ProRule annotationAdd BLAST255
Domaini299 – 351AGC-kinase C-terminalAdd BLAST53

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0616. Eukaryota.
ENOG410XPQQ. LUCA.
HOGENOMiHOG000233033.
HOVERGENiHBG108317.
InParanoidiP27791.
PhylomeDBiP27791.

Family and domain databases

InterProiView protein in InterPro
IPR000961. AGC-kinase_C.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
PfamiView protein in Pfam
PF00069. Pkinase. 1 hit.
SMARTiView protein in SMART
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiView protein in 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.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P27791-1) [UniParc]FASTAAdd to basket
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.

« Hide

        10         20         30         40         50
MGNAAAAKKG SEQESVKEFL AKAKEDFLKK WEDPSQNTAQ LDHFDRIKTL
60 70 80 90 100
GTGSFGRVML VKHKESGNHY AMKILDKQKV VKLKQIEHTL NEKRILQAVN
110 120 130 140 150
FPFLVKLEFS FKDNSNLYMV MEYVPGGEMF SHLRRIGRFS EPHARFYAAQ
160 170 180 190 200
IVLTFEYLHS LDLIYRDLKP ENLLIDQQGY IQVTDFGFAK RVKGRTWTLC
210 220 230 240 250
GTPEYLAPEI ILSKGYNKAV DWWALGVLIY EMAAGYPPFF ADQPIQIYEK
260 270 280 290 300
IVSGKVRFPS HFSSDLKDLL RNLLQVDLTK RFGNLKNGVN DIKNHKWFAT
310 320 330 340 350
TDWIAIYQRK VEAPFIPKFK GPGDTSNFDD YEEEEIRVSI NEKCGKEFTE

F
Length:351
Mass (Da):40,620
Last modified:January 23, 2007 - v2
Checksum:i4763ACD074AB2384
GO
Isoform 2 (identifier: P27791-2) [UniParc]FASTAAdd to basket
Also known as: Cs

The sequence of this isoform differs from the canonical sequence as follows:
     1-15: MGNAAAAKKGSEQES → MASNSND

Show »
Length:343
Mass (Da):39,879
Checksum:iA41B65C8AB162401
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0132771 – 15MGNAA…SEQES → MASNSND in isoform 2. 1 PublicationAdd BLAST15

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X57986 mRNA. Translation: CAA41052.1.
AY375243 mRNA. Translation: AAQ81631.1.
PIRiS16240. OKRT2C.
UniGeneiRn.20.

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiKAPCA_RAT
AccessioniPrimary (citable) accession number: P27791
Secondary accession number(s): Q6UA68
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1992
Last sequence update: January 23, 2007
Last modified: June 7, 2017
This is version 161 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families