KGP1_RABIT
ID KGP1_RABIT Reviewed; 671 AA.
AC O77676;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=cGMP-dependent protein kinase 1;
DE Short=cGK 1;
DE Short=cGK1;
DE EC=2.7.11.12;
GN Name=PRKG1;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=New Zealand white; TISSUE=Heart;
RX PubMed=10565812;
RA Kumar R., Joyner R.W., Komalavilas P., Lincoln T.M.;
RT "Analysis of expression of cGMP-dependent protein kinase in rabbit heart
RT cells.";
RL J. Pharmacol. Exp. Ther. 291:967-975(1999).
RN [2]
RP FUNCTION IN PHOSPHORYLATION OF RGS4.
RX PubMed=16885398; DOI=10.1152/ajpcell.00103.2006;
RA Huang J., Zhou H., Mahavadi S., Sriwai W., Murthy K.S.;
RT "Inhibition of Galphaq-dependent PLC-beta1 activity by PKG and PKA is
RT mediated by phosphorylation of RGS4 and GRK2.";
RL Am. J. Physiol. 292:C200-C208(2007).
CC -!- FUNCTION: Serine/threonine protein kinase that acts as key mediator of
CC the nitric oxide (NO)/cGMP signaling pathway. GMP binding activates
CC PRKG1, which phosphorylates serines and threonines on many cellular
CC proteins. Numerous protein targets for PRKG1 phosphorylation are
CC implicated in modulating cellular calcium, but the contribution of each
CC of these targets may vary substantially among cell types. Proteins that
CC are phosphorylated by PRKG1 regulate platelet activation and adhesion,
CC smooth muscle contraction, cardiac function, gene expression, feedback
CC of the NO-signaling pathway, and other processes involved in several
CC aspects of the CNS like axon guidance, hippocampal and cerebellar
CC learning, circadian rhythm and nociception. Smooth muscle relaxation is
CC mediated through lowering of intracellular free calcium, by
CC desensitization of contractile proteins to calcium, and by decrease in
CC the contractile state of smooth muscle or in platelet activation.
CC Regulates intracellular calcium levels via several pathways:
CC phosphorylates IRAG1 and inhibits IP3-induced Ca(2+) release from
CC intracellular stores, phosphorylation of KCNMA1 (BKCa) channels
CC decreases intracellular Ca(2+) levels, which leads to increased opening
CC of this channel. PRKG1 phosphorylates the canonical transient receptor
CC potential channel (TRPC) family which inactivates the associated inward
CC calcium current. Another mode of action of NO/cGMP/PKGI signaling
CC involves PKGI-mediated inactivation of the Ras homolog gene family
CC member A (RhoA). Phosphorylation of RHOA by PRKG1 blocks the action of
CC this protein in myriad processes: regulation of RHOA translocation;
CC decreasing contraction; controlling vesicle trafficking, reduction of
CC myosin light chain phosphorylation resulting in vasorelaxation.
CC Activation of PRKG1 by NO signaling alters also gene expression in a
CC number of tissues. In smooth muscle cells, increased cGMP and PRKG1
CC activity influence expression of smooth muscle-specific contractile
CC proteins, levels of proteins in the NO/cGMP signaling pathway, down-
CC regulation of the matrix proteins osteopontin and thrombospondin-1 to
CC limit smooth muscle cell migration and phenotype. Regulates
CC vasodilator-stimulated phosphoprotein (VASP) functions in platelets and
CC smooth muscle (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:16885398}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.12;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.12;
CC -!- ACTIVITY REGULATION: In the absence of cGMP, PRKG1 activity is
CC suppressed by autoinhibitory contacts. {ECO:0000250}.
CC -!- SUBUNIT: Isoform alpha: parallel homodimer or heterodimer and also
CC heterotetramer. Interacts directly with PPP1R12A. Non-covalent dimer of
CC dimer of PRKG1-PRKG1 and PPP1R12A-PPP1R12A. This interaction targets
CC PRKG1 to stress fibers to mediate smooth muscle cell relaxation and
CC vasodilation in responses to rises in cGMP (By similarity). Isoform
CC beta: antiparallel homodimer. Part of cGMP kinase signaling complex at
CC least composed of ACTA2/alpha-actin, CNN1/calponin H1,
CC PLN/phospholamban, PRKG1 and ITPR1. Interacts with IRAG1 (By
CC similarity). Forms a stable complex with ITPR1, IRAG1, and isoform beta
CC of PRKG1 (By similarity). Interacts with TRPC7 (via ankyrin repeat
CC domain) (By similarity). Isoform alpha interacts with RGS2 (By
CC similarity). Interacts with GTF2I (By similarity). {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Note=Colocalized with
CC TRPC7 in the plasma membrane. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Alpha; Synonyms=CGK1-alpha;
CC IsoId=O77676-1; Sequence=Displayed;
CC Name=Beta; Synonyms=CGK1-beta;
CC IsoId=O77676-2; Sequence=Not described;
CC -!- DOMAIN: Composed of an N-terminal leucine-zipper domain followed by an
CC autoinhibitory domain, which mediate homodimer formation and inhibit
CC kinase activity, respectively. Next, two cGMP-binding domains are
CC followed by the catalytic domain at the C-terminus. Binding of cGMP to
CC cGMP-binding domains results in a conformational change that activates
CC kinase activity by removing the autoinhibitory domain from the
CC catalytic cleft leaving the catalytic domain free to phosphorylate
CC downstream substrates. Isoforms alpha and beta have identical cGMP-
CC binding and catalytic domains but differ in their leucine zipper and
CC autoinhibitory sequences and therefore differ in their dimerization
CC substrates and kinase enzyme activity (By similarity). {ECO:0000250}.
CC -!- DOMAIN: Heterotetramerization is mediated by the interaction between a
CC coiled-coil of PRKG1 and the leucine/isoleucine zipper of PPP1R12A/MBS,
CC the myosin-binding subunit of the myosin phosphatase. {ECO:0000250}.
CC -!- PTM: Autophosphorylation increases kinase activity. {ECO:0000250}.
CC -!- PTM: 65 kDa monomer is produced by proteolytic cleavage. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. cGMP subfamily. {ECO:0000305}.
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DR EMBL; AF076969; AAC31192.1; -; mRNA.
DR RefSeq; NP_001075511.1; NM_001082042.2. [O77676-1]
DR AlphaFoldDB; O77676; -.
DR BMRB; O77676; -.
DR SMR; O77676; -.
DR STRING; 9986.ENSOCUP00000009871; -.
DR GeneID; 100008694; -.
DR KEGG; ocu:100008694; -.
DR CTD; 5592; -.
DR eggNOG; KOG0614; Eukaryota.
DR InParanoid; O77676; -.
DR OrthoDB; 401933at2759; -.
DR BRENDA; 2.7.11.12; 1749.
DR Proteomes; UP000001811; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005246; F:calcium channel regulator activity; ISS:UniProtKB.
DR GO; GO:0030553; F:cGMP binding; IEA:UniProtKB-KW.
DR GO; GO:0004692; F:cGMP-dependent protein kinase activity; ISS:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0090331; P:negative regulation of platelet aggregation; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
DR GO; GO:0043087; P:regulation of GTPase activity; ISS:UniProtKB.
DR CDD; cd00038; CAP_ED; 2.
DR CDD; cd05572; STKc_cGK; 1.
DR Gene3D; 2.60.120.10; -; 2.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR002374; cGMP_dep_kinase.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR018488; cNMP-bd_CS.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR031831; PKcGMP_CC.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR InterPro; IPR035014; STKc_cGK.
DR Pfam; PF00027; cNMP_binding; 2.
DR Pfam; PF16808; PKcGMP_CC; 1.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF000559; cGMP-dep_kinase; 1.
DR PRINTS; PR00104; CGMPKINASE.
DR SMART; SM00100; cNMP; 2.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF51206; SSF51206; 2.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00889; CNMP_BINDING_2; 2.
DR PROSITE; PS50042; CNMP_BINDING_3; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Acetylation; Allosteric enzyme; Alternative splicing; ATP-binding; cGMP;
KW cGMP-binding; Coiled coil; Cytoplasm; Disulfide bond; Kinase;
KW Nucleotide-binding; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:P00516"
FT CHAIN 2..671
FT /note="cGMP-dependent protein kinase 1"
FT /id="PRO_0000086116"
FT DOMAIN 360..619
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 620..671
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT REGION 2..102
FT /note="Required for dimerization"
FT /evidence="ECO:0000250"
FT REGION 9..44
FT /note="Leucine-zipper"
FT REGION 50..75
FT /note="Autoinhibitory domain"
FT /evidence="ECO:0000250"
FT REGION 103..220
FT /note="cGMP-binding, high affinity"
FT /evidence="ECO:0000250"
FT REGION 221..341
FT /note="cGMP-binding, low affinity"
FT /evidence="ECO:0000250"
FT REGION 635..671
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 2..59
FT /evidence="ECO:0000250"
FT COMPBIAS 651..671
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 484
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 167..170
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q13976"
FT BINDING 177..178
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:Q13976"
FT BINDING 282
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q13976"
FT BINDING 291..294
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q13976"
FT BINDING 301..302
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q13976"
FT BINDING 336
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:Q13976"
FT BINDING 366..374
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 390
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:P00516"
FT MOD_RES 59
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P00516"
FT MOD_RES 515
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P0C605"
FT DISULFID 43
FT /note="Interchain"
FT /evidence="ECO:0000250"
FT VARIANT 558
FT /note="F -> S"
SQ SEQUENCE 671 AA; 76454 MW; F8E50992F39C0D81 CRC64;
MSELEEDFAK ILMLKEERIK ELEKRLSEKE EEIQELKRKL HKCQSVLPVP STHIGPRTTR
AQGISAEPQT YRSFHDLRQA FRKFTKFERS KDLIKEAILD NDFMKNLELS QIQEIVDCMY
PVEYGKDSCI IKEGDVGSLA YVMEDGKVEV TKEGVKLCTM GPGKVFGELA ILYNCTRTAT
VKTLVNVKLW AIDRQCFQTI MMRTGLIKHT EYMEFLKSVP TFQSLPEEIL SKLADVLEET
HYENEEYSIR QGARGDTFFI ISKGKVNVTR EDSPSEDPIF LRTLGKGDWF GEKALQGEDV
RTANVIAAEA VTCLVIDRDS FKHLIGGLDD VSNKAYEDAE AKAKYEAEAA FFANLKLSDF
NIIDTLGVGG FGRVELVQLK SEESKTFAMK ILKKRHIVDT RQQEHIRSEK QIMQGAHSDF
IVRLYRTFKD SKYLYMLMEA CLGGELWTIL RDRGSFEDST TRFYTACVVE AFAYLHSKGI
IYRDLKPENL ILDHRGYAKL VDFGFAKKIG FGKKTWTFCG TPEYVAPEII LNKGHDISAD
YWSLGILMYE LLTGSPPFSG PDPMKTYNII LRGIDMIEFP KKIAKNAANL IKKLCRDNPS
ERLGNLKNGV KDIQKHKWFE GFNWEGLRKG TLTPPIIPSV ASPTDTSNFD GFPEDNDEPP
PDDNSGWDID F
