P0C605 (KGP1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
cGMP-dependent protein kinase 1
Short name=cGK 1
Short name=cGK1
EC=2.7.11.12

Alternative name(s):
cGMP-dependent protein kinase I
Short name=cGKI

Gene names

Name:	Prkg1
Synonyms:	Prkg1b, Prkgr1a, Prkgr1b

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	671 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	Serine/threonine protein kinasethat acts as key mediator of the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins. Numerous protein targets for PRKG1 phosphorylation are implicated in modulating cellular calcium, but the contribution of each of these targets may vary substantially among cell types. Proteins that are phosphorylated by PRKG1 regulate platelet activation and adhesion, smooth muscle contraction, cardiac function, gene expression, feedback of the NO-signaling pathway, and other processes involved in several aspects of the CNS like axon guidance, hippocampal and cerebellar learning, circadian rhythm and nociception. Smoth muscle relaxation is mediated through lowering of intracellular free calcium, by desensitization of contractile proteins to calcium, and by decrease in the contractile state of smooth muscle or in platelet activation. Regulates intracellular calcium levels via several pathways: phosphorylates MRVI1/IRAG and inhibits IP3-induced Ca2+ release from intracellular stores, phosphorylation of KCNMA1 (BKCa) channels decreases intracellular Ca2+ levels, which leads to increased opening of this channel. PRKG1 phosphorylates the canonical transient receptor potential channel (TRPC) family which inactivates the associated inward calcium current. Another mode of action of NO/cGMP/PKGI signaling involves PKGI-mediated inactivation of the Ras homolog gene family member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of this protein in myriad processes: regulation of RHOA translocation; decreasing contraction; controlling vesicle trafficking, reduction of myosin light chain phosphorylation resulting in vasorelaxation. Activation of PRKG1 by NO signaling alters also gene expression in a number of tissues. In smooth muscle cells, increased cGMP and PRKG1 activity influence expression of smooth muscle-specific contractile proteins, levels of proteins in the NO/cGMP signaling pathway, down-regulation of the matrix proteins osteopontin and thrombospondin-1 to limit smooth muscle cell migration and phenotype. Regulates vasodilator-stimulated phosphoprotein (VASP) functions in platelets and smooth muscle. Ref.4 Ref.5 Ref.6 Ref.7 Ref.10
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	In the absence of cGMP, PRKG1 activity is suppressed by autoinhibitory contacts By similarity.
Subunit structure	Isoform alpha: parallel homodimer or heterodimer and also heterotetramer. Interacts directly with PPP1R12A. Non-covalent dimer of dimer of PRKG1-PRKG1 and PPP1R12A-PPP1R12A. This interaction targets PRKG1 to stress fibers to mediate smooth muscle cell relaxation and vasodilation in responses to rises in cGMP By similarity. Isoform beta: antiparallel homodimer. Part of cGMP kinase signaling complex at least composed of ACTA2/alpha-actin, CNN1/calponin H1, PLN/phospholamban, PRKG1 and ITPR1 By similarity. Interacts with MRVI1. Forms a stable complex with ITPR1, MRVI1, and isoform beta of PRKG1 By similarity. Interacts with TRPC7 (via ankyrin repeat domain) By similarity. Isoform alpha interacts with RGS2 By similarity. Interacts with GTF2I By similarity. Ref.9
Subcellular location	Cytoplasm By similarity. Note: Colocalized with TRPC7 in the plasma membrane By similarity.
Tissue specificity	Detected in cerebellum, hippocampus, dorsomedial hypothalamus, medulla, subcommissural organ, cerebral cortex, amygdala, habenulae, various hypothalamic regions, olfactory bulb, pituitary gland, and retina. Isoform alpha is prominent in the cerebellum and medulla, whereas isoform Beta is predominant in the cortex, hippocampus, hypothalamus, and olfactory bulb. Ref.8
Domain	Composed of an N-terminal leucine-zipper domain followed by an autoinhibitory domain, which mediate homodimer formation and inhibit kinase activity, respectively. Next, two cGMP-binding domains are followed by the catalytic domain at the C-terminus. Binding of cGMP to cGMP-binding domains results in a conformational change that activates kinase activity by removing the autoinhibitory domain from the catalytic cleft leaving the catalytic domain free to phosphorylate downstream substrates. Isoforms alpha and beta have identical cGMP-binding and catalytic domains but differ in their leucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity By similarity. Heterotetramerization is mediated by the interaction between a coiled-coil of PRKG1 and the leucine/isoleucine zipper of PPP1R12A/MBS, the myosin-binding subunit of the myosin phosphatase By similarity.
Post-translational modification	Autophosphorylation increases kinase activity By similarity. 65 kDa monomer is produced by proteolytic cleavage By similarity.
Disruption phenotype	Leads to premature death at approximately 6 weeks of age, presumably due to smooth muscle dysfunction. These mice show multiple defects including impaired smooth muscle relaxation, disturbed gastrointestinal motility and enhanced platelet adhesion. Ref.4 Ref.6
Sequence similarities	Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cGMP subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 2 cyclic nucleotide-binding domains. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing
Domain	Coiled coil
Ligand	ATP-binding Nucleotide-binding cGMP cGMP-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Disulfide bond Phosphoprotein
Technical term	Allosteric enzyme Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	dendrite development Inferred from mutant phenotype. Source: MGI forebrain development Inferred from mutant phenotype. Source: MGI negative regulation of platelet aggregation Inferred from sequence or structural similarity. Source: UniProtKB neuron migration Inferred from mutant phenotype. Source: MGI regulation of GTPase activity Inferred from sequence or structural similarity. Source: UniProtKB signal transduction Inferred from direct assay. Source: UniProtKB
Cellular component	Golgi apparatus Inferred from direct assay. Source: UniProtKB plasma membrane Inferred from mutant phenotype. Source: BHF-UCL
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW cGMP binding Inferred from direct assay. Source: UniProtKB cGMP-dependent protein kinase activity Inferred from direct assay. Source: UniProtKB calcium channel regulator activity Inferred from sequence or structural similarity. Source: UniProtKB protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Alpha (identifier: P0C605-1)

Also known as: CGK1-alpha;

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 Beta (identifier: P0C605-2)

Also known as: CGK1-beta;

The sequence of this isoform differs from the canonical sequence as follows:
     1-89: MSELEEDFAK...AFRKFTKSER → MGTLRDLQYA...TLPFYPKSPQ

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 671	670	cGMP-dependent protein kinase 1		PRO_0000314022
Regions
	Domain	9 – 44	36	Leucine-zipper
	Domain	360 – 619	260	Protein kinase
	Domain	620 – 671	52	AGC-kinase C-terminal
	Nucleotide binding	167 – 170	4	cAMP or cGMP By similarity
	Nucleotide binding	177 – 178	2	cAMP or cGMP By similarity
	Nucleotide binding	366 – 374	9	ATP By similarity
	Region	2 – 102	101	Required for dimerization By similarity
	Region	50 – 75	26	Autoinhibitory domain By similarity
	Region	103 – 220	118	cGMP-binding, high affinity By similarity
	Region	221 – 341	121	cGMP-binding, low affinity By similarity
Sites
	Active site	484	1	Proton acceptor By similarity
	Binding site	390	1	ATP By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylserine By similarity
	Modified residue	59	1	Phosphothreonine; by autocatalysis By similarity
	Modified residue	515	1	Phosphothreonine By similarity
	Disulfide bond	43		Interchain By similarity
Natural variations
	Alternative sequence	1 – 89	89	MSELE…TKSER → MGTLRDLQYALQEKIEELRQ RDALIDELELELDQKDELIQ KLQNELDKYRSVIRPATQQA QKQSASTLQGEPRTKRQAIS AEPTAFDIQDLSHVTLPFYP KSPQ in isoform Beta.		VSP_038715

Sequences

	Sequence		Length	Mass (Da)
	Isoform Alpha (CGK1-alpha) [UniParc]. Last modified January 15, 2008. Version 1. Checksum: 51878E2D27F26A22	FASTA	671	76,350
	10 20 30 40 50 60 MSELEEDFAK ILMLKEERIK ELEKRLSEKE EEIQELKRKL HKCQSVLPVP STHIGPRTTR 70 80 90 100 110 120 AQGISAEPQT YRSFHDLRQA FRKFTKSERS KDLIKEAILD NDFMKNLELS QIQEIVDCMY 130 140 150 160 170 180 PVEYGKDSCI IKEGDVGSLV YVMEDGKVEV TKEGVKLCTM GPGKVFGELA ILYNCTRTAT 190 200 210 220 230 240 VKTLVNVKLW AIDRQCFQTI MMRTGLIKHT EYMEFLKSVP TFQSLPDEIL SKLADVLEET 250 260 270 280 290 300 HYENGEYIIR QGARGDTFFI ISKGQVNVTR EDSPSEDPVF LRTLGKGDWF GEKALQGEDV 310 320 330 340 350 360 RTANVIAAEA VTCLVIDRDS FKHLIGGLDD VSNKAYEDAE AKAKYEAEAA FFANLKLSDF 370 380 390 400 410 420 NIIDTLGVGG FGRVELVQLK SEESKTFAMK ILKKRHIVDT RQQEHIRSEK QIMQGAHSDF 430 440 450 460 470 480 IVRLYRTFKD SKYLYMLMEA CLGGELWTIL RDRGSFEDST TRFYTACVVE AFAYLHSKGI 490 500 510 520 530 540 IYRDLKPENL ILDHRGYAKL VDFGFAKKIG FGKKTWTFCG TPEYVAPEII LNKGHDISAD 550 560 570 580 590 600 YWSLGILMYE LLTGSPPFSG PDPMKTYNII LRGIDMIEFP KKIAKNAANL IKKLCRDNPS 610 620 630 640 650 660 ERLGNLKNGV KDIQKHKWFE GFNWEGLRKG TLTPPIIPSV ASPTDTSNFD SFPEDSDEPP 670 PDDNSGWDID F
	Isoform Beta (CGK1-beta) [UniParc] [UniParc]. Checksum: A0281F3530936016	FASTA	686	77,790
	10 20 30 40 50 60 MGTLRDLQYA LQEKIEELRQ RDALIDELEL ELDQKDELIQ KLQNELDKYR SVIRPATQQA 70 80 90 100 110 120 QKQSASTLQG EPRTKRQAIS AEPTAFDIQD LSHVTLPFYP KSPQSKDLIK EAILDNDFMK 130 140 150 160 170 180 NLELSQIQEI VDCMYPVEYG KDSCIIKEGD VGSLVYVMED GKVEVTKEGV KLCTMGPGKV 190 200 210 220 230 240 FGELAILYNC TRTATVKTLV NVKLWAIDRQ CFQTIMMRTG LIKHTEYMEF LKSVPTFQSL 250 260 270 280 290 300 PDEILSKLAD VLEETHYENG EYIIRQGARG DTFFIISKGQ VNVTREDSPS EDPVFLRTLG 310 320 330 340 350 360 KGDWFGEKAL QGEDVRTANV IAAEAVTCLV IDRDSFKHLI GGLDDVSNKA YEDAEAKAKY 370 380 390 400 410 420 EAEAAFFANL KLSDFNIIDT LGVGGFGRVE LVQLKSEESK TFAMKILKKR HIVDTRQQEH 430 440 450 460 470 480 IRSEKQIMQG AHSDFIVRLY RTFKDSKYLY MLMEACLGGE LWTILRDRGS FEDSTTRFYT 490 500 510 520 530 540 ACVVEAFAYL HSKGIIYRDL KPENLILDHR GYAKLVDFGF AKKIGFGKKT WTFCGTPEYV 550 560 570 580 590 600 APEIILNKGH DISADYWSLG ILMYELLTGS PPFSGPDPMK TYNIILRGID MIEFPKKIAK 610 620 630 640 650 660 NAANLIKKLC RDNPSERLGN LKNGVKDIQK HKWFEGFNWE GLRKGTLTPP IIPSVASPTD 670 680 TSNFDSFPED SDEPPPDDNS GWDIDF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cyclic AMP- and cyclic GMP-dependent protein kinases differ in their regulation of cyclic AMP response element-dependent gene transcription." Collins S.P., Uhler M.D. J. Biol. Chem. 274:8391-8404(1999) [PubMed: 10085070] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BETA). Strain: C57BL/6. Tissue: Brain.
[2]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed: 19468303] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[3]	"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] (ISOFORM BETA).
[4]	"Defective smooth muscle regulation in cGMP kinase I-deficient mice." Pfeifer A., Klatt P., Massberg S., Ny L., Sausbier M., Hirneiss C., Wang G.X., Korth M., Aszodi A., Andersson K.E., Krombach F., Mayerhofer A., Ruth P., Fassler R., Hofmann F. EMBO J. 17:3045-3051(1998) [PubMed: 9606187] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[5]	"Phosphorylation-dependent inhibition of protein phosphatase-1 by G-substrate: a Purkinje cell substrate of the cyclic GMP-dependent protein kinase." Hall K.U., Collins S.P., Gamm D.M., Massa E., Depaoli-Roach A.A., Uhler M.D. J. Biol. Chem. 274:3485-3495(1999) [PubMed: 9920894] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF PPP1R17. Tissue: Brain.
[6]	"Increased adhesion and aggregation of platelets lacking cyclic guanosine 3',5'-monophosphate kinase I." Massberg S., Sausbier M., Klatt P., Bauer M., Pfeifer A., Siess W., Fassler R., Ruth P., Krombach F., Hofmann F. J. Exp. Med. 189:1255-1264(1999) [PubMed: 10209042] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[7]	"Mechanisms of NO/cGMP-dependent vasorelaxation." Sausbier M., Schubert R., Voigt V., Hirneiss C., Pfeifer A., Korth M., Kleppisch T., Ruth P., Hofmann F. Circ. Res. 87:825-830(2000) [PubMed: 11055988] [Abstract] Cited for: FUNCTION IN THE REGULATION OF VASCULAR TONE.
[8]	"Distribution of cGMP-dependent protein kinase type I and its isoforms in the mouse brain and retina." Feil S., Zimmermann P., Knorn A., Brummer S., Schlossmann J., Hofmann F., Feil R. Neuroscience 135:863-868(2005) [PubMed: 16154279] [Abstract] Cited for: TISSUE SPECIFICITY.
[9]	"IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and thrombus formation." Antl M., von Bruehl M.-L., Eiglsperger C., Werner M., Konrad I., Kocher T., Wilm M., Hofmann F., Massberg S., Schlossmann J. Blood 109:552-559(2007) [PubMed: 16990611] [Abstract] Cited for: INTERACTION WITH MRVI1.
[10]	"cGMP-dependent protein kinase type I is implicated in the regulation of the timing and quality of sleep and wakefulness." Langmesser S., Franken P., Feil S., Emmenegger Y., Albrecht U., Feil R. PLoS ONE 4:E4238-E4238(2009) [PubMed: 19156199] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF084547 mRNA. Translation: AAD16044.1. AC102751 Genomic DNA. No translation available. AC103405 Genomic DNA. No translation available. AC108399 Genomic DNA. No translation available. AC116507 Genomic DNA. No translation available. AC119158 Genomic DNA. No translation available. AC122548 Genomic DNA. No translation available. BC113162 mRNA. Translation: AAI13163.1.
IPI	IPI00129693. IPI00458024.
RefSeq	NP_001013855.1. NM_001013833.3. NP_035290.1. NM_011160.3.
UniGene	Mm.381170. Mm.381172.
3D structure databases
ProteinModelPortal	P0C605.
SMR	P0C605. Positions 9-44, 79-658.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-29981N.
STRING	P0C605.
Proteomic databases
PRIDE	P0C605.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000065067; ENSMUSP00000067576; ENSMUSG00000052920. ENSMUST00000073581; ENSMUSP00000073268; ENSMUSG00000052920.
GeneID	19091.
KEGG	mmu:19091.
UCSC	uc008heo.1. mouse.
Organism-specific databases
CTD	5592.
MGI	MGI:108174. Prkg1.
Phylogenomic databases
HOVERGEN	HBG006211.
OMA	HHIVETR.
OrthoDB	EOG4V9TQ7.
PhylomeDB	P0C605.
Gene expression databases
ArrayExpress	P0C605.
Bgee	P0C605.
CleanEx	MM_PRKG1.
Genevestigator	P0C605.
Family and domain databases
InterPro	IPR000961. AGC-kinase_C. IPR016232. cGMP-dependent_protein_kinase. IPR002374. cGMP_dep_kinase. IPR018490. cNMP-bd-like. IPR018488. cNMP-bd_CS. IPR000595. cNMP-bd_dom. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR014710. RmlC-like_jellyroll. IPR017442. Se/Thr_kinase-like_dom. IPR008271. Ser/Thr_kinase_AS. IPR002290. Ser/Thr_kinase_dom. [Graphical view]
Gene3D	G3DSA:2.60.120.10. RmlC-like_jellyroll. 2 hits.
KO	K07376.
Pfam	PF00027. cNMP_binding. 2 hits. PF00069. Pkinase. 1 hit. [Graphical view]
PIRSF	PIRSF000559. cGMP-dep_kinase. 1 hit.
PRINTS	PR00104. CGMPKINASE.
SMART	SM00100. cNMP. 2 hits. SM00133. S_TK_X. 1 hit. SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF51206. cNMP_binding. 2 hits. SSF56112. Kinase_like. 1 hit.
PROSITE	PS51285. AGC_KINASE_CTER. 1 hit. PS00888. CNMP_BINDING_1. 2 hits. PS00889. CNMP_BINDING_2. 2 hits. PS50042. CNMP_BINDING_3. 2 hits. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	295648.
SOURCE	Search...

Entry information

Entry name

KGP1_MOUSE

Accession

Primary (citable) accession number: P0C605
Secondary accession number(s): Q14DK6, Q9Z0Z0

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 15, 2008
Last sequence update:	January 15, 2008
Last modified:	January 25, 2012
This is version 47 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program