P27791 (KAPCA_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
cAMP-dependent protein kinase catalytic subunit alpha
Short name=PKA C-alpha
EC=2.7.11.11

Gene names

Name:

Prkaca

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	351 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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, TRPC1 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+. TRPC1 activation by phosphorylation promotes Ca2+ influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (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. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. 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 By similarity. Ref.4
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	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.
Subunit structure	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. Ref.5
Subcellular location	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.
Tissue specificity	Ubiquitously expressed. Isoform 2 is round spermatid specific. Ref.1 Ref.3
Developmental stage	In spermatids, isoform 1 is expressed until spermatids become elutriated, whereafter isoform 2 is expressed. Ref.3
Post-translational modification	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.5
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane Mitochondrion Nucleus
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Nucleotide-binding cAMP
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Lipoprotein Myristate Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	negative regulation of meiotic cell cycle Inferred from direct assay PubMed 16816331. Source: RGD peptidyl-serine phosphorylation Inferred from direct assay PubMed 15546918. Source: RGD regulation of cellular respiration Inferred from direct assay PubMed 12562968. Source: RGD regulation of synaptic transmission, glutamatergic Inferred from direct assay PubMed 12562968. Source: RGD
Cellular_component	Golgi apparatus Inferred from direct assay PubMed 12086672. Source: RGD cAMP-dependent protein kinase complex Inferred from direct assay PubMed 11907174PubMed 16816331. Source: RGD cytosol Traceable author statement. Source: Reactome membrane Inferred from direct assay PubMed 12086672. Source: RGD mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell nucleoplasm Traceable author statement. Source: Reactome perinuclear region of cytoplasm Inferred from direct assay PubMed 18550536. Source: RGD plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cAMP-dependent protein kinase activity Inferred from direct assay PubMed 11907174PubMed 15546918PubMed 16816331. Source: RGD protein kinase A regulatory subunit binding Inferred by curator PubMed 16816331. Source: RGD
Complete GO annotation...

Alternative products

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:
     1-15: MGNAAAAKKGSEQES → MASNSND

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed By similarity

Chain

2 – 351

350

cAMP-dependent protein kinase catalytic subunit alpha

PRO_0000086055

Regions

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

Sites

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

35

1

Phosphoserine By similarity

Modified residue

49

1

Phosphothreonine By similarity

Modified residue

140

1

Phosphoserine Ref.5

Modified residue

196

1

Phosphothreonine By similarity

Modified residue

198

1

Phosphothreonine; by PDPK1 Ref.5

Modified residue

202

1

Phosphothreonine By similarity

Modified residue

339

1

Phosphoserine By similarity

Lipidation

2

1

N-myristoyl glycine Ref.2

Natural variations

Alternative sequence

1 – 15

15

MGNAA…SEQES → MASNSND in isoform 2.

VSP_013277

Secondary structure

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351

Helix Strand Turn

Details...

Helix

16 – 32

17

Helix

41 – 43

3

Beta strand

44 – 52

9

Beta strand

57 – 63

7

Turn

64 – 66

3

Beta strand

69 – 76

8

Helix

77 – 82

6

Helix

86 – 96

11

Beta strand

107 – 112

6

Beta strand

114 – 122

9

Helix

129 – 136

8

Helix

141 – 159

19

Turn

160 – 162

3

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 – 307

5

Turn

345 – 350

6

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (C-alpha-1) [UniParc]. Last modified January 23, 2007. Version 2. Checksum: 4763ACD074AB2384	FASTA	351	40,620
	10 20 30 40 50 60 MGNAAAAKKG SEQESVKEFL AKAKEDFLKK WEDPSQNTAQ LDHFDRIKTL GTGSFGRVML 70 80 90 100 110 120 VKHKESGNHY AMKILDKQKV VKLKQIEHTL NEKRILQAVN FPFLVKLEFS FKDNSNLYMV 130 140 150 160 170 180 MEYVPGGEMF SHLRRIGRFS EPHARFYAAQ IVLTFEYLHS LDLIYRDLKP ENLLIDQQGY 190 200 210 220 230 240 IQVTDFGFAK RVKGRTWTLC GTPEYLAPEI ILSKGYNKAV DWWALGVLIY EMAAGYPPFF 250 260 270 280 290 300 ADQPIQIYEK IVSGKVRFPS HFSSDLKDLL RNLLQVDLTK RFGNLKNGVN DIKNHKWFAT 310 320 330 340 350 TDWIAIYQRK VEAPFIPKFK GPGDTSNFDD YEEEEIRVSI NEKCGKEFTE F
	Isoform 2 (Cs) [UniParc]. Checksum: A41B65C8AB162401	FASTA	343	39,879
	10 20 30 40 50 60 MASNSNDVKE FLAKAKEDFL KKWEDPSQNT AQLDHFDRIK TLGTGSFGRV MLVKHKESGN 70 80 90 100 110 120 HYAMKILDKQ KVVKLKQIEH TLNEKRILQA VNFPFLVKLE FSFKDNSNLY MVMEYVPGGE 130 140 150 160 170 180 MFSHLRRIGR FSEPHARFYA AQIVLTFEYL HSLDLIYRDL KPENLLIDQQ GYIQVTDFGF 190 200 210 220 230 240 AKRVKGRTWT LCGTPEYLAP EIILSKGYNK AVDWWALGVL IYEMAAGYPP FFADQPIQIY 250 260 270 280 290 300 EKIVSGKVRF PSHFSSDLKD LLRNLLQVDL TKRFGNLKNG VNDIKNHKWF ATTDWIAIYQ 310 320 330 340 RKVEAPFIPK FKGPGDTSNF DDYEEEEIRV SINEKCGKEF TEF

References

[1]	"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.
[2]	"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.
[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. Strain: Wistar.
[4]	"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.
[5]	"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.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X57986 mRNA. Translation: CAA41052.1.
AY375243 mRNA. Translation: AAQ81631.1.

IPI

IPI00200013.
IPI00555215.

PIR

OKRT2C. S16240.

UniGene

Rn.20.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3TNP	X-ray	2.30	C/F	2-351	[»]
3TNQ	X-ray	3.10	B	2-351	[»]

ProteinModelPortal

P27791.

SMR

P27791. Positions 13-351.

ModBase

Search...

Protein-protein interaction databases

IntAct

P27791. 1 interaction.

MINT

MINT-4564372.

PTM databases

PhosphoSite

P27791.

Proteomic databases

PaxDb

P27791.

PRIDE

P27791.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Organism-specific databases

RGD

3389. Prkaca.

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233033.

HOVERGEN

HBG108317.

OrthoDB

EOG4RXZ0C.

Enzyme and pathway databases

BRENDA

2.7.11.11. 5301.

Reactome

REACT_109781. Immune System.
REACT_110573. Disease.
REACT_111984. Signal Transduction.
REACT_113568. Metabolism.

Gene expression databases

ArrayExpress

P27791.

Genevestigator

P27791.

GermOnline

ENSRNOG00000005257. Rattus norvegicus.

Family and domain databases

InterPro

IPR000961. AGC-kinase_C.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 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.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P27791.

ChEMBL

CHEMBL3390.

Entry information

Entry name

KAPCA_RAT

Accession

Primary (citable) accession number: P27791
Secondary accession number(s): Q6UA68

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1992
Last sequence update:	January 23, 2007
Last modified:	April 3, 2013
This is version 126 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program