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Protein

cGMP-dependent protein kinase 1

Gene

Prkg1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Serine/threonine protein kinase that 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. Smooth 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.5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

In the absence of cGMP, PRKG1 activity is suppressed by autoinhibitory contacts.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei282cGMP 2By similarity1
Binding sitei336cAMP or cGMP 2By similarity1
Binding sitei390ATPPROSITE-ProRule annotation1
Active sitei484Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi167 – 170cAMP or cGMP 1By similarity4
Nucleotide bindingi177 – 178cAMP or cGMP 1By similarity2
Nucleotide bindingi291 – 294cAMP or cGMP 2By similarity4
Nucleotide bindingi301 – 302cAMP or cGMP 2By similarity2
Nucleotide bindingi366 – 374ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • calcium channel regulator activity Source: UniProtKB
  • cGMP binding Source: UniProtKB
  • cGMP-dependent protein kinase activity Source: UniProtKB
  • identical protein binding Source: MGI
  • protein kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: MGI

GO - Biological processi

  • cGMP-mediated signaling Source: MGI
  • dendrite development Source: MGI
  • forebrain development Source: MGI
  • negative regulation of platelet aggregation Source: UniProtKB
  • negative regulation of smooth muscle contraction Source: MGI
  • negative regulation of vascular associated smooth muscle cell migration Source: MGI
  • negative regulation of vascular smooth muscle cell proliferation Source: MGI
  • neuron migration Source: MGI
  • protein phosphorylation Source: UniProtKB
  • regulation of GTPase activity Source: UniProtKB
  • relaxation of vascular smooth muscle Source: MGI
  • signal transduction Source: UniProtKB

Keywordsi

Molecular functionAllosteric enzyme, Kinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, cGMP, cGMP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.12 3474
ReactomeiR-MMU-392517 Rap1 signalling
R-MMU-418457 cGMP effects

Names & Taxonomyi

Protein namesi
Recommended name:
cGMP-dependent protein kinase 1 (EC:2.7.11.12)
Short name:
cGK 1
Short name:
cGK1
Alternative name(s):
cGMP-dependent protein kinase I
Short name:
cGKI
Gene namesi
Name:Prkg1
Synonyms:Prkg1b, Prkgr1a, Prkgr1b
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 19

Organism-specific databases

MGIiMGI:108174 Prkg1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Disruption phenotypei

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.2 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00003140222 – 671cGMP-dependent protein kinase 1Add BLAST670

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylserineBy similarity1
Disulfide bondi43InterchainBy similarity
Modified residuei59Phosphothreonine; by autocatalysisBy similarity1
Modified residuei515PhosphothreonineCombined sources1

Post-translational modificationi

Autophosphorylation increases kinase activity.By similarity
65 kDa monomer is produced by proteolytic cleavage.By similarity

Keywords - PTMi

Acetylation, Disulfide bond, Phosphoprotein

Proteomic databases

PeptideAtlasiP0C605
PRIDEiP0C605

PTM databases

iPTMnetiP0C605
PhosphoSitePlusiP0C605

Expressioni

Tissue specificityi

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.1 Publication

Gene expression databases

BgeeiENSMUSG00000052920
CleanExiMM_PRKG1
ExpressionAtlasiP0C605 baseline and differential
GenevisibleiP0C605 MM

Interactioni

Subunit structurei

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).By similarity

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi202372, 3 interactors
DIPiDIP-29981N
IntActiP0C605, 5 interactors
MINTiP0C605

Structurei

3D structure databases

ProteinModelPortaliP0C605
SMRiP0C605
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini360 – 619Protein kinasePROSITE-ProRule annotationAdd BLAST260
Domaini620 – 671AGC-kinase C-terminalAdd BLAST52

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 102Required for dimerizationBy similarityAdd BLAST101
Regioni9 – 44Leucine-zipperAdd BLAST36
Regioni50 – 75Autoinhibitory domainBy similarityAdd BLAST26
Regioni103 – 220cGMP-binding, high affinityBy similarityAdd BLAST118
Regioni221 – 341cGMP-binding, low affinityBy similarityAdd BLAST121

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili2 – 59By similarityAdd BLAST58

Domaini

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).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

Sequence similaritiesi

Keywords - Domaini

Coiled coil

Phylogenomic databases

GeneTreeiENSGT00810000125385
HOGENOMiHOG000233033
HOVERGENiHBG006211
InParanoidiP0C605
KOiK07376
OMAiEPQTHQD
OrthoDBiEOG091G0S9R
PhylomeDBiP0C605
TreeFamiTF313261

Family and domain databases

CDDicd00038 CAP_ED, 2 hits
cd05572 STKc_cGK, 1 hit
Gene3Di2.60.120.10, 2 hits
InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR002374 cGMP_dep_kinase
IPR018490 cNMP-bd-like
IPR018488 cNMP-bd_CS
IPR000595 cNMP-bd_dom
IPR011009 Kinase-like_dom_sf
IPR031831 PKcGMP_CC
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR014710 RmlC-like_jellyroll
IPR008271 Ser/Thr_kinase_AS
IPR035014 STKc_cGK
PfamiView protein in Pfam
PF00027 cNMP_binding, 2 hits
PF16808 PKcGMP_CC, 1 hit
PF00069 Pkinase, 1 hit
PIRSFiPIRSF000559 cGMP-dep_kinase, 1 hit
PRINTSiPR00104 CGMPKINASE
SMARTiView protein in SMART
SM00100 cNMP, 2 hits
SM00133 S_TK_X, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF51206 SSF51206, 2 hits
SSF56112 SSF56112, 1 hit
PROSITEiView protein in 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

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 Alpha (identifier: P0C605-1) [UniParc]FASTAAdd to basket
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.

« Hide

        10         20         30         40         50
MSELEEDFAK ILMLKEERIK ELEKRLSEKE EEIQELKRKL HKCQSVLPVP
60 70 80 90 100
STHIGPRTTR AQGISAEPQT YRSFHDLRQA FRKFTKSERS KDLIKEAILD
110 120 130 140 150
NDFMKNLELS QIQEIVDCMY PVEYGKDSCI IKEGDVGSLV YVMEDGKVEV
160 170 180 190 200
TKEGVKLCTM GPGKVFGELA ILYNCTRTAT VKTLVNVKLW AIDRQCFQTI
210 220 230 240 250
MMRTGLIKHT EYMEFLKSVP TFQSLPDEIL SKLADVLEET HYENGEYIIR
260 270 280 290 300
QGARGDTFFI ISKGQVNVTR EDSPSEDPVF LRTLGKGDWF GEKALQGEDV
310 320 330 340 350
RTANVIAAEA VTCLVIDRDS FKHLIGGLDD VSNKAYEDAE AKAKYEAEAA
360 370 380 390 400
FFANLKLSDF NIIDTLGVGG FGRVELVQLK SEESKTFAMK ILKKRHIVDT
410 420 430 440 450
RQQEHIRSEK QIMQGAHSDF IVRLYRTFKD SKYLYMLMEA CLGGELWTIL
460 470 480 490 500
RDRGSFEDST TRFYTACVVE AFAYLHSKGI IYRDLKPENL ILDHRGYAKL
510 520 530 540 550
VDFGFAKKIG FGKKTWTFCG TPEYVAPEII LNKGHDISAD YWSLGILMYE
560 570 580 590 600
LLTGSPPFSG PDPMKTYNII LRGIDMIEFP KKIAKNAANL IKKLCRDNPS
610 620 630 640 650
ERLGNLKNGV KDIQKHKWFE GFNWEGLRKG TLTPPIIPSV ASPTDTSNFD
660 670
SFPEDSDEPP PDDNSGWDID F
Length:671
Mass (Da):76,350
Last modified:January 15, 2008 - v1
Checksum:i51878E2D27F26A22
GO
Isoform Beta (identifier: P0C605-2) [UniParc] [UniParc]FASTAAdd to basket
Also known as: CGK1-beta

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

Show »
Length:686
Mass (Da):77,790
Checksum:iA0281F3530936016
GO

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0387151 – 89MSELE…TKSER → MGTLRDLQYALQEKIEELRQ RDALIDELELELDQKDELIQ KLQNELDKYRSVIRPATQQA QKQSASTLQGEPRTKRQAIS AEPTAFDIQDLSHVTLPFYP KSPQ in isoform Beta. 2 PublicationsAdd BLAST89

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS29745.1 [P0C605-1]
CCDS29746.1 [P0C605-2]
RefSeqiNP_001013855.1, NM_001013833.3 [P0C605-1]
NP_035290.1, NM_011160.3 [P0C605-2]
XP_006526831.1, XM_006526768.3 [P0C605-1]
UniGeneiMm.381170

Genome annotation databases

EnsembliENSMUST00000065067; ENSMUSP00000067576; ENSMUSG00000052920 [P0C605-1]
ENSMUST00000073581; ENSMUSP00000073268; ENSMUSG00000052920 [P0C605-2]
GeneIDi19091
KEGGimmu:19091
UCSCiuc008heo.2 mouse [P0C605-2]
uc008hep.2 mouse [P0C605-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiKGP1_MOUSE
AccessioniPrimary (citable) accession number: P0C605
Secondary accession number(s): Q14DK6, Q9Z0Z0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 15, 2008
Last sequence update: January 15, 2008
Last modified: May 23, 2018
This is version 103 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families
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