cAMP-dependent protein kinase type I-alpha regulatory subunit

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Reviewed, UniProtKB/Swiss-Prot P10644 (KAP0_HUMAN)

Last modified December 16, 2008. Version 108. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    cAMP-dependent protein kinase type I-alpha regulatory subunit
Alternative name(s):
    Tissue-specific extinguisher 1
      Short name=TSE1

Gene names

Name:	PRKAR1A
Synonyms:	PKR1, PRKAR1, TSE1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	381 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Subunit structure	The inactive form of the enzyme is composed of two regulatory chains and two catalytic chains. Activation by cAMP produces two active catalytic monomers and a regulatory dimer that binds four cAMP molecules. PRKAR1A also interacts with RFC2; the complex may be involved in cell survival. Interacts with AKAP4. Ref.8
Tissue specificity	Four types of regulatory chains are found: I-alpha, I-beta, II-alpha, and II-beta. Their expression varies among tissues and is in some cases constitutive and in others inducible.
Post-translational modification	The pseudophosphorylation site binds to the substrate-binding region of the catalytic chain, resulting in the inhibition of its activity.
Involvement in disease	Defects in PRKAR1A are the cause of Carney complex type 1 (CNC1) [MIM:160980]. CNC is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumors, and psammomatous melanotic schwannomas. Ref.15 Ref.16 Defects in PRKAR1A are the cause of intracardiac myxoma [MIM:255960]. Inheritance is autosomal recessive. Defects in PRKAR1A are the cause of primary pigmented nodular adrenocortical disease type 1 (PPNAD1) [MIM:610489]. Primary pigmented nodular adrenocortical disease is a rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. PPNAD1 is most often diagnosed in patients with Carney complex, but it can also be observed in patients without other manifestations or familial history. Ref.7
Sequence similarities	Belongs to the cAMP-dependent kinase regulatory chain family. Contains 2 cyclic nucleotide-binding domains.

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Ontologies

Keywords
Disease	Disease mutation
Domain	Repeat
Ligand	Nucleotide-binding cAMP cAMP-binding
PTM	Acetylation Phosphoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	hormone-mediated signaling Inferred from Experiment. Source: Reactome regulation of protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro regulation of transcription from RNA polymerase II promoter Traceable author statement. Source: ProtInc
Cellular component	cAMP-dependent protein kinase complex Inferred from electronic annotation. Source: InterPro
Molecular function	cAMP binding Inferred from electronic annotation. Source: UniProtKB-KW cAMP-dependent protein kinase regulator activity Ref.1 Traceable author statement. Source: ProtInc protein binding Ref.8 Inferred from physical interaction. Source: IntAct
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct
MCRS1	Q96EZ8	1	EBI-476431,EBI-348259
NUAK1	O60285	1	EBI-476431,EBI-1046789
PRKACA	P17612	2	EBI-476431,EBI-476586
RFC2	P35250	4	EBI-476431,EBI-476409
TUSC4	Q8WTW4	1	EBI-476431,EBI-1043552
UBE2M	P61081	1	EBI-476431,EBI-1041660

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 381

381

cAMP-dependent protein kinase type I-alpha regulatory subunit

PRO_0000205377

Regions

Nucleotide binding

137 – 254

118

cAMP 1

Nucleotide binding

255 – 381

127

cAMP 2

Region

1 – 136

136

Dimerization and phosphorylation

Motif

96 – 100

Pseudophosphorylation motif

Sites

Binding site

202

cAMP 1

Binding site

211

cAMP 1

Binding site

326

cAMP 2

Binding site

335

cAMP 2

Amino acid modifications

Modified residue

N-acetylmethionine Ref.6

Modified residue

Phosphoserine By similarity

Modified residue

Phosphoserine Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14

Modified residue

101

Phosphoserine By similarity

Disulfide bond

Interchain (with C-39) By similarity

Disulfide bond

Interchain (with C-18) By similarity

Natural variations

Natural variant

S → N in CNC1; exhibits increased PKA activity which is attributed to decreased binding to cAMP and/or the catalytic subunit. Ref.16

VAR_046894

Natural variant

R → C in CNC1; exhibits increased PKA activity which is attributed to decreased binding to cAMP and/or the catalytic subunit. Ref.15 Ref.16

VAR_046895

Natural variant

146

R → S in CNC1; exhibits increased PKA activity which is attributed to decreased binding to cAMP and/or the catalytic subunit. Ref.16

VAR_046896

Natural variant

183

D → Y in CNC1; exhibits increased PKA activity which is attributed to decreased binding to cAMP and/or the catalytic subunit. Ref.16

VAR_046897

Natural variant

213

A → D in CNC1; exhibits increased PKA activity which is attributed to decreased binding to cAMP and/or the catalytic subunit. Ref.16

VAR_046898

Natural variant

289

G → W in CNC1; exhibits increased PKA activity which is attributed to decreased binding to cAMP and/or the catalytic subunit. Ref.16

VAR_046899

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Sequences

Sequence

Length

Mass (Da)

Tools

P10644-1 [UniParc].

Last modified July 1, 1989. Version 1.
Checksum: 2D04F08CE8857A6D
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FASTA

381

42,982

        10         20         30         40         50         60 
MESGSTAASE EARSLRECEL YVQKHNIQAL LKDSIVQLCT ARPERPMAFL REYFERLEKE 

        70         80         90        100        110        120 
EAKQIQNLQK AGTRTDSRED EISPPPPNPV VKGRRRRGAI SAEVYTEEDA ASYVRKVIPK 

       130        140        150        160        170        180 
DYKTMAALAK AIEKNVLFSH LDDNERSDIF DAMFSVSFIA GETVIQQGDE GDNFYVIDQG 

       190        200        210        220        230        240 
ETDVYVNNEW ATSVGEGGSF GELALIYGTP RAATVKAKTN VKLWGIDRDS YRRILMGSTL 

       250        260        270        280        290        300 
RKRKMYEEFL SKVSILESLD KWERLTVADA LEPVQFEDGQ KIVVQGEPGD EFFIILEGSA 

       310        320        330        340        350        360 
AVLQRRSENE EFVEVGRLGP SDYFGEIALL MNRPRAATVV ARGPLKCVKL DRPRFERVLG 

       370        380 
PCSDILKRNI QQYNSFVSLS V

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning, cDNA structure and deduced amino acid sequence for a type I regulatory subunit of cAMP-dependent protein kinase from human testis." Sandberg M., Tasken K., Oeyen O., Hansson V., Jahnsen T. Biochem. Biophys. Res. Commun. 149:939-945(1987) [PubMed: 3426618] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[2]	"The two mRNA forms for the type I alpha regulatory subunit of cAMP-dependent protein kinase from human testis are due to the use of different polyadenylation site signals." Sandberg M., Skalhegg B., Jahnsen T. Biochem. Biophys. Res. Commun. 167:323-330(1990) [PubMed: 2310396] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[3]	"Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A." Jones K.W., Shapero M.H., Chevrette M., Fournier R.E. Cell 66:861-872(1991) [PubMed: 1889088] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"The human gene for the regulatory subunit RI alpha of cyclic adenosine 3', 5'-monophosphate-dependent protein kinase: two distinct promoters provide differential regulation of alternately spliced messenger ribonucleic acids." Solberg R., Sandberg M., Natarajan V., Torjesen P.A., Hansson V., Jahnsen T., Tasken K. Endocrinology 138:169-181(1997) [PubMed: 8977401] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lymph and Uterus.
[6]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed: 12665801] [Abstract] Cited for: PROTEIN SEQUENCE OF 1-13, ACETYLATION AT MET-1. Tissue: Platelet.
[7]	"Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease." Groussin L., Jullian E., Perlemoine K., Louvel A., Leheup B., Luton J.P., Bertagna X., Bertherat J. J. Clin. Endocrinol. Metab. 87:4324-4329(2002) [PubMed: 12213893] [Abstract] Cited for: INVOLVEMENT IN PPNAD1.
[8]	"The second subunit of the replication factor C complex (RFC40) and the regulatory subunit (RIalpha) of protein kinase A form a protein complex promoting cell survival." Gupte R.S., Weng Y., Liu L., Lee M.Y. Cell Cycle 4:323-329(2005) [PubMed: 15655353] [Abstract] Cited for: INTERACTION WITH RFC2.
[9]	"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks." Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M. Cell 127:635-648(2006) [PubMed: 17081983] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, MASS SPECTROMETRY. Tissue: Epithelium.
[10]	"Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry." Molina H., Horn D.M., Tang N., Mathivanan S., Pandey A. Proc. Natl. Acad. Sci. U.S.A. 104:2199-2204(2007) [PubMed: 17287340] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, MASS SPECTROMETRY.
[11]	"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column." Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y. Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, MASS SPECTROMETRY.
[12]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, MASS SPECTROMETRY.
[13]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, MASS SPECTROMETRY.
[14]	"Large-scale phosphoproteome analysis of human liver tissue by enrichment and fractionation of phosphopeptides with strong anion exchange chromatography." Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D., Zou H., Gu J. Proteomics 8:1346-1361(2008) [PubMed: 18318008] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, MASS SPECTROMETRY. Tissue: Liver.
[15]	"Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice." Veugelers M., Wilkes D., Burton K., McDermott D.A., Song Y., Goldstein M.M., La Perle K., Vaughan C.J., O'Hagan A., Bennett K.R., Meyer B.J., Legius E., Karttunen M., Norio R., Kaariainen H., Lavyne M., Neau J.-P., Richter G. Basson C.T. Proc. Natl. Acad. Sci. U.S.A. 101:14222-14227(2004) [PubMed: 15371594] [Abstract] Cited for: VARIANT CNC1 CYS-74.
[16]	"In vitro functional studies of naturally occurring pathogenic PRKAR1A mutations that are not subject to nonsense mRNA decay." Greene E.L., Horvath A.D., Nesterova M., Giatzakis C., Bossis I., Stratakis C.A. Hum. Mutat. 29:633-639(2008) [PubMed: 18241045] [Abstract] Cited for: VARIANTS CNC1 ASN-9; SER-146; TYR-183; ASP-213 AND TRP-289, CHARACTERIZATION OF VARIANTS CNC1 ASN-9; CYS-74; SER-146; TYR-183; ASP-213 AND TRP-289.
+	Additional computationally mapped references.

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Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

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Cross-references

Sequence databases
	M18468 mRNA. Translation: AAB50922.1. M33336 mRNA. Translation: AAB50921.1. S54705 mRNA. No translation available. S54707 mRNA. No translation available. S54709 mRNA. No translation available. S54711 mRNA. No translation available. Y07642 mRNA. Translation: CAA68925.1. BC036285 mRNA. Translation: AAH36285.1. BC093042 mRNA. Translation: AAH93042.1.
PIR	OKHU1R. A34627.
RefSeq	NP_002725.1. NP_997636.1. NP_997637.1.
UniGene	Hs.280342 Hs.659124
3D structure databases
HSSP	HSSP built from PDB template 1RGS based on UniProtKB P00514.
SMR	P10644. Positions 14-63, 111-378.
ModBase	Search...
Protein-protein interaction databases
IntAct	P10644. 12 interactions.
PTM databases
PhosphoSite	P10644.
2-D gel databases
OGP	P10644.
REPRODUCTION-2DPAGE	IPI00021831.
Proteomic databases
PeptideAtlas	P10644.
PRIDE	P10644.
Genome annotation databases
Ensembl	ENSG00000108946. Homo sapiens. [Contig view]
GeneID	5573.
KEGG	hsa:5573.
Organism-specific databases
GeneCards	GC17P064019.
H-InvDB	HIX0014116.
HGNC	HGNC:9388. PRKAR1A.
MIM	160980. phenotype. 188830. gene. 255960. phenotype. 610489. phenotype.
Orphanet	615. Atrial myxoma, familial. 1359. Carney complex.
PharmGKB	PA33754.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	P10644.
HOVERGEN	P10644.
Enzyme and pathway databases
Reactome	REACT_1505. Integration of energy metabolism.
Gene expression databases
ArrayExpress	P10644.
CleanEx	HS_PRKAR1A.
GermOnline	ENSG00000108946. Homo sapiens.
Family and domain databases
InterPro	IPR003117. cAMP-dep_prot_kin_reg_I/II_a/b. IPR002373. cAMP/cGMP_kin. IPR000595. cNMP_bd. IPR012198. PK_regulatory. IPR014710. RmlC-like_jellyroll. [Graphical view]
Gene3D	G3DSA:2.60.120.10. RmlC-like_jellyroll. 2 hits.
Pfam	PF00027. cNMP_binding. 2 hits. PF02197. RIIa. 1 hit. [Graphical view]
PIRSF	PIRSF000548. PK_regulatory. 1 hit.
PRINTS	PR00103. CAMPKINASE.
SMART	SM00100. cNMP. 2 hits. SM00394. RIIa. 1 hit. [Graphical view]
PROSITE	PS00888. CNMP_BINDING_1. 2 hits. PS00889. CNMP_BINDING_2. 2 hits. PS50042. CNMP_BINDING_3. 2 hits. [Graphical view]
ProtoNet	Search...
Other Resources
LinkHub	P10644.
NextBio	21602.
SOURCE	Search...

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Entry information

Entry name

KAP0_HUMAN

Accession

Primary (citable) accession number: P10644
Secondary accession number(s): Q567S7

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	July 1, 1989
Last modified:	December 16, 2008
This is version 108 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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Human chromosome 17: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Keywords

Gene Ontology (GO)

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

2-D gel databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents