KGP1_HUMAN
ID KGP1_HUMAN Reviewed; 671 AA.
AC Q13976; A5YM56; B3KSF3; E2PU10; P14619; Q5JP05; Q5JSJ6; Q6P5T7;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 212.
DE RecName: Full=cGMP-dependent protein kinase 1;
DE Short=cGK 1;
DE Short=cGK1;
DE EC=2.7.11.12;
DE AltName: Full=cGMP-dependent protein kinase I;
DE Short=cGKI;
GN Name=PRKG1; Synonyms=PRKG1B, PRKGR1A, PRKGR1B;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM BETA).
RC TISSUE=Placenta;
RX PubMed=2792381; DOI=10.1016/0014-5793(89)81114-7;
RA Sandberg M., Natarajan V., Ronander I., Kalderon D., Walter U.,
RA Lohmann S.M., Jahnsen T.;
RT "Molecular cloning and predicted full-length amino acid sequence of the
RT type I beta isozyme of cGMP-dependent protein kinase from human placenta.
RT Tissue distribution and developmental changes in rat.";
RL FEBS Lett. 255:321-329(1989).
RN [2]
RP SEQUENCE REVISION.
RA Sandberg M.;
RL Submitted (OCT-1989) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM ALPHA).
RC TISSUE=Lung;
RX PubMed=8613202; DOI=10.1161/01.hyp.27.3.552;
RA Tamura N., Itoh H., Ogawa Y., Nakagawa O., Harada M., Chun T., Suga S.,
RA Yoshimasa T., Nakao K.;
RT "cDNA cloning and gene expression of human type Ialpha cGMP-dependent
RT protein kinase.";
RL Hypertension 27:552-557(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RX PubMed=9192852; DOI=10.1006/geno.1997.4743;
RA Orstavik S., Natarajan V., Tasken K., Jahnsen T., Sandberg M.;
RT "Characterization of the human gene encoding the type I alpha and type I
RT beta cGMP-dependent protein kinase (PRKG1).";
RL Genomics 42:311-318(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM BETA).
RC TISSUE=Cervix;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM BETA).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP FUNCTION IN PHOSPHORYLATION OF VASP.
RX PubMed=8182057; DOI=10.1016/s0021-9258(17)36652-8;
RA Butt E., Abel K., Krieger M., Palm D., Hoppe V., Hoppe J., Walter U.;
RT "cAMP- and cGMP-dependent protein kinase phosphorylation sites of the focal
RT adhesion vasodilator-stimulated phosphoprotein (VASP) in vitro and in
RT intact human platelets.";
RL J. Biol. Chem. 269:14509-14517(1994).
RN [11]
RP INTERACTION WITH PPP1R12A, SUBUNIT, MUTAGENESIS OF LEU-12; ILE-19; LEU-26;
RP ILE-33 AND LEU-40, AND FUNCTION.
RX PubMed=10567269; DOI=10.1126/science.286.5444.1583;
RA Surks H.K., Mochizuki N., Kasai Y., Georgescu S.P., Tang K.M., Ito M.,
RA Lincoln T.M., Mendelsohn M.E.;
RT "Regulation of myosin phosphatase by a specific interaction with cGMP-
RT dependent protein kinase Ialpha.";
RL Science 286:1583-1587(1999).
RN [12]
RP FUNCTION IN PHOSPHORYLATION OF RHOA.
RX PubMed=11162591; DOI=10.1006/bbrc.2000.4194;
RA Sawada N., Itoh H., Yamashita J., Doi K., Inoue M., Masatsugu K.,
RA Fukunaga Y., Sakaguchi S., Sone M., Yamahara K., Yurugi T., Nakao K.;
RT "cGMP-dependent protein kinase phosphorylates and inactivates RhoA.";
RL Biochem. Biophys. Res. Commun. 280:798-805(2001).
RN [13]
RP FUNCTION IN PHOSPHORYLATION OF GTF2I, AND INTERACTION WITH GTF2I.
RX PubMed=12082086; DOI=10.1074/jbc.m112332200;
RA Casteel D.E., Zhuang S., Gudi T., Tang J., Vuica M., Desiderio S.,
RA Pilz R.B.;
RT "cGMP-dependent protein kinase I beta physically and functionally interacts
RT with the transcriptional regulator TFII-I.";
RL J. Biol. Chem. 277:32003-32014(2002).
RN [14]
RP FUNCTION IN PHOSPHORYLATION OF PDE5.
RX PubMed=11723116; DOI=10.1074/jbc.m106562200;
RA Rybalkin S.D., Rybalkina I.G., Feil R., Hofmann F., Beavo J.A.;
RT "Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in
RT smooth muscle cells.";
RL J. Biol. Chem. 277:3310-3317(2002).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF RGS2, AND INTERACTION WITH RGS2.
RX PubMed=14608379; DOI=10.1038/nm958;
RA Tang K.M., Wang G.R., Lu P., Karas R.H., Aronovitz M., Heximer S.P.,
RA Kaltenbronn K.M., Blumer K.J., Siderovski D.P., Zhu Y., Mendelsohn M.E.;
RT "Regulator of G-protein signaling-2 mediates vascular smooth muscle
RT relaxation and blood pressure.";
RL Nat. Med. 9:1506-1512(2003).
RN [16]
RP FUNCTION.
RX PubMed=15194681; DOI=10.1074/jbc.m405957200;
RA Wooldridge A.A., MacDonald J.A., Erdodi F., Ma C., Borman M.A.,
RA Hartshorne D.J., Haystead T.A.J.;
RT "Smooth muscle phosphatase is regulated in vivo by exclusion of
RT phosphorylation of threonine 696 of MYPT1 by phosphorylation of Serine 695
RT in response to cyclic nucleotides.";
RL J. Biol. Chem. 279:34496-34504(2004).
RN [17]
RP FUNCTION IN THE INHIBITION OF PLATELET AGGREGATION, FUNCTION IN
RP PHOSPHORYLATION OF IRAG1, SUBCELLULAR LOCATION, AND INTERACTION WITH IRAG1
RP AND ITPR1.
RX PubMed=16990611; DOI=10.1182/blood-2005-10-026294;
RA Antl M., von Bruehl M.-L., Eiglsperger C., Werner M., Konrad I., Kocher T.,
RA Wilm M., Hofmann F., Massberg S., Schlossmann J.;
RT "IRAG mediates NO/cGMP-dependent inhibition of platelet aggregation and
RT thrombus formation.";
RL Blood 109:552-559(2007).
RN [18]
RP INTERACTION WITH PPP1R12A.
RX PubMed=17904578; DOI=10.1016/j.jmb.2007.08.049;
RA Lee E., Hayes D.B., Langsetmo K., Sundberg E.J., Tao T.C.;
RT "Interactions between the leucine-zipper motif of cGMP-dependent protein
RT kinase and the C-terminal region of the targeting subunit of myosin light
RT chain phosphatase.";
RL J. Mol. Biol. 373:1198-1212(2007).
RN [19]
RP INTERACTION WITH PPP1R12A, AND SUBUNIT.
RX PubMed=18782776; DOI=10.1074/jbc.m804916200;
RA Sharma A.K., Zhou G.-P., Kupferman J., Surks H.K., Christensen E.N.,
RA Chou J.J., Mendelsohn M.E., Rigby A.C.;
RT "Probing the interaction between the coiled coil leucine zipper of cGMP-
RT dependent protein kinase Ialpha and the C terminus of the myosin binding
RT subunit of the myosin light chain phosphatase.";
RL J. Biol. Chem. 283:32860-32869(2008).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [21]
RP REVIEW.
RX PubMed=20716671; DOI=10.1124/pr.110.002907;
RA Francis S.H., Busch J.L., Corbin J.D., Sibley D.;
RT "cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide
RT and cGMP action.";
RL Pharmacol. Rev. 62:525-563(2010).
RN [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [23]
RP FUNCTION (ISOFORM ALPHA) IN PHOSPHORYLATION OF TRPC7, INTERACTION WITH
RP TRPC7, AND SUBCELLULAR LOCATION.
RX PubMed=21402151; DOI=10.1016/j.cellsig.2011.03.005;
RA Yuasa K., Matsuda T., Tsuji A.;
RT "Functional regulation of transient receptor potential canonical 7 by cGMP-
RT dependent protein kinase Ialpha.";
RL Cell. Signal. 23:1179-1187(2011).
RN [24]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=22223895; DOI=10.1074/mcp.m111.015131;
RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T.,
RA Giglione C.;
RT "Comparative large-scale characterisation of plant vs. mammal proteins
RT reveals similar and idiosyncratic N-alpha acetylation features.";
RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012).
RN [25]
RP STRUCTURE BY NMR OF 2-58, INTERACTION WITH PPP1R12A, SUBUNIT, AND
RP COILED-COIL.
RX PubMed=16131665; DOI=10.1110/ps.051528905;
RA Schnell J.R., Zhou G.-P., Zweckstetter M., Rigby A.C., Chou J.J.;
RT "Rapid and accurate structure determination of coiled-coil domains using
RT NMR dipolar couplings: application to cGMP-dependent protein kinase
RT Ialpha.";
RL Protein Sci. 14:2421-2428(2005).
RN [26] {ECO:0007744|PDB:3NMD}
RP X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS) OF 4-55 (ISOFORM BETA), AND SUBUNIT.
RX PubMed=20826808; DOI=10.1074/jbc.c110.161430;
RA Casteel D.E., Smith-Nguyen E.V., Sankaran B., Roh S.H., Pilz R.B., Kim C.;
RT "A crystal structure of the cyclic GMP-dependent protein kinase I{beta}
RT dimerization/docking domain reveals molecular details of isoform-specific
RT anchoring.";
RL J. Biol. Chem. 285:32684-32688(2010).
RN [27] {ECO:0007744|PDB:3OCP, ECO:0007744|PDB:3OD0, ECO:0007744|PDB:3OGJ}
RP X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 92-227 (ISOFORM BETA) IN COMPLEX
RP WITH CGMP AND CAMP.
RX PubMed=21526164; DOI=10.1371/journal.pone.0018413;
RA Kim J.J., Casteel D.E., Huang G., Kwon T.H., Ren R.K., Zwart P.,
RA Headd J.J., Brown N.G., Chow D.C., Palzkill T., Kim C.;
RT "Co-crystal structures of PKG Ibeta (92-227) with cGMP and cAMP reveal the
RT molecular details of cyclic-nucleotide binding.";
RL PLoS ONE 6:E18413-E18413(2011).
RN [28] {ECO:0007744|PDB:4QX5, ECO:0007744|PDB:4QXK}
RP X-RAY CRYSTALLOGRAPHY (1.32 ANGSTROMS) OF 204-354 (ISOFORM BETA) IN COMPLEX
RP WITH CAMP AND CGMP.
RX PubMed=25271401; DOI=10.1021/bi501012v;
RA Huang G.Y., Gerlits O.O., Blakeley M.P., Sankaran B., Kovalevsky A.Y.,
RA Kim C.;
RT "Neutron diffraction reveals hydrogen bonds critical for cGMP-selective
RT activation: insights for cGMP-dependent protein kinase agonist design.";
RL Biochemistry 53:6725-6727(2014).
RN [29] {ECO:0007744|PDB:4KU7, ECO:0007744|PDB:4KU8}
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 204-354 (ISOFORM BETA) IN COMPLEX
RP WITH CGMP, AND MUTAGENESIS OF LEU-281; ARG-282; THR-302 AND TYR-336.
RX PubMed=24239458; DOI=10.1016/j.str.2013.09.021;
RA Huang G.Y., Kim J.J., Reger A.S., Lorenz R., Moon E.W., Zhao C.,
RA Casteel D.E., Bertinetti D., Vanschouwen B., Selvaratnam R.,
RA Pflugrath J.W., Sankaran B., Melacini G., Herberg F.W., Kim C.;
RT "Structural basis for cyclic-nucleotide selectivity and cGMP-selective
RT activation of PKG I.";
RL Structure 22:116-124(2014).
RN [30]
RP VARIANTS [LARGE SCALE ANALYSIS] VAL-249 AND SER-267.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [31]
RP VARIANT AAT8 GLN-177, VARIANTS PHE-474 AND ALA-666, AND CHARACTERIZATION OF
RP VARIANT AAT8 GLN-177.
RX PubMed=23910461; DOI=10.1016/j.ajhg.2013.06.019;
RG GenTAC Registry Consortium;
RG National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project;
RA Guo D.C., Regalado E., Casteel D.E., Santos-Cortez R.L., Gong L., Kim J.J.,
RA Dyack S., Horne S.G., Chang G., Jondeau G., Boileau C., Coselli J.S.,
RA Li Z., Leal S.M., Shendure J., Rieder M.J., Bamshad M.J., Nickerson D.A.,
RA Kim C., Milewicz D.M.;
RT "Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic
RT aneurysms and acute aortic dissections.";
RL Am. J. Hum. Genet. 93:398-404(2013).
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. {ECO:0000269|PubMed:10567269,
CC ECO:0000269|PubMed:11162591, ECO:0000269|PubMed:11723116,
CC ECO:0000269|PubMed:12082086, ECO:0000269|PubMed:14608379,
CC ECO:0000269|PubMed:15194681, ECO:0000269|PubMed:16990611,
CC ECO:0000269|PubMed:8182057}.
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.
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. Isoform beta: antiparallel
CC homodimer. Part of cGMP kinase signaling complex at least composed of
CC ACTA2/alpha-actin, CNN1/calponin H1, PLN/phospholamban, PRKG1 and ITPR1
CC (By similarity). Interacts with IRAG1. Forms a stable complex with
CC ITPR1, IRAG1, and isoform beta of PRKG1. Interacts with TRPC7 (via
CC ankyrin repeat domain). Isoform alpha interacts with RGS2. Interacts
CC with GTF2I. {ECO:0000250, ECO:0000269|PubMed:10567269,
CC ECO:0000269|PubMed:12082086, ECO:0000269|PubMed:14608379,
CC ECO:0000269|PubMed:16131665, ECO:0000269|PubMed:16990611,
CC ECO:0000269|PubMed:17904578, ECO:0000269|PubMed:18782776,
CC ECO:0000269|PubMed:20826808, ECO:0000269|PubMed:21402151}.
CC -!- INTERACTION:
CC Q13976; Q13873: BMPR2; NbExp=2; IntAct=EBI-3952014, EBI-527196;
CC Q13976; Q86V42: FAM124A; NbExp=4; IntAct=EBI-3952014, EBI-744506;
CC Q13976; P25791: LMO2; NbExp=4; IntAct=EBI-3952014, EBI-739696;
CC Q13976; O76074: PDE5A; NbExp=4; IntAct=EBI-3952014, EBI-9023531;
CC Q13976; O15015: ZNF646; NbExp=4; IntAct=EBI-3952014, EBI-745608;
CC Q13976-2; O94989: ARHGEF15; NbExp=3; IntAct=EBI-4280187, EBI-740691;
CC Q13976-2; P25791-3: LMO2; NbExp=3; IntAct=EBI-4280187, EBI-11959475;
CC Q13976-2; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-4280187, EBI-16439278;
CC Q13976-2; Q13976-2: PRKG1; NbExp=3; IntAct=EBI-4280187, EBI-4280187;
CC Q13976-2; Q9NYW8: RBAK; NbExp=3; IntAct=EBI-4280187, EBI-1210429;
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=3;
CC Name=Alpha; Synonyms=CGK1-alpha;
CC IsoId=Q13976-1; Sequence=Displayed;
CC Name=Beta; Synonyms=CGK1-beta;
CC IsoId=Q13976-2, P14619-1;
CC Sequence=VSP_038714;
CC Name=3;
CC IsoId=Q13976-3; Sequence=VSP_055541, VSP_055542;
CC -!- TISSUE SPECIFICITY: Primarily expressed in lung and placenta.
CC {ECO:0000269|PubMed:9192852}.
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.
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.
CC -!- PTM: Autophosphorylation increases kinase activity.
CC -!- PTM: 65 kDa monomer is produced by proteolytic cleavage. {ECO:0000250}.
CC -!- DISEASE: Aortic aneurysm, familial thoracic 8 (AAT8) [MIM:615436]: A
CC disease characterized by permanent dilation of the thoracic aorta
CC usually due to degenerative changes in the aortic wall. It is primarily
CC associated with a characteristic histologic appearance known as 'medial
CC necrosis' or 'Erdheim cystic medial necrosis' in which there is
CC degeneration and fragmentation of elastic fibers, loss of smooth muscle
CC cells, and an accumulation of basophilic ground substance.
CC {ECO:0000269|PubMed:23910461}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: The 3D structures in complex with cGMP and cAMP describe
CC the hydrogen bonding interactions that modulate high selectivity for
CC cGMP in the CNB-B domain, and reveal that all these contacts are
CC disrupted in the structure with cAMP, explaining the low affinity of
CC the enzyme for cAMP and the fact that cAMP can only weakly activate
CC PKG. {ECO:0000269|PubMed:25271401}.
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; Y07512; CAA68810.1; -; mRNA.
DR EMBL; D45864; BAA08297.1; -; mRNA.
DR EMBL; AK093436; BAG52715.1; -; mRNA.
DR EMBL; EF560730; ABQ59040.1; -; mRNA.
DR EMBL; Z92867; CAB07436.1; -; Genomic_DNA.
DR EMBL; Z92869; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92870; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92871; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92872; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92873; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92874; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92875; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92876; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92877; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92878; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92879; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92880; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92881; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92882; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92883; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92884; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92885; CAB07436.1; JOINED; Genomic_DNA.
DR EMBL; Z92868; CAB07437.1; -; Genomic_DNA.
DR EMBL; Z92869; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92870; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92871; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92872; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92873; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92874; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92875; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92876; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92877; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92878; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92879; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92880; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92881; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92882; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92883; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92884; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; Z92885; CAB07437.1; JOINED; Genomic_DNA.
DR EMBL; AL391378; CAI39626.1; -; Genomic_DNA.
DR EMBL; AC009986; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AC022537; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AC022025; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AC027118; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AL731537; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AL928686; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AL157399; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AC026228; CAI39626.1; JOINED; Genomic_DNA.
DR EMBL; AL928686; CAI40743.1; -; Genomic_DNA.
DR EMBL; AC009986; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AC022537; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AL731537; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AL391378; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AL157399; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AC027118; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AC026228; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AC022025; CAI40743.1; JOINED; Genomic_DNA.
DR EMBL; AL157399; CAI41305.1; -; Genomic_DNA.
DR EMBL; AC022025; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AC009986; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AL928686; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AL731537; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AL391378; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AC027118; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AC026228; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AC022537; CAI41305.1; JOINED; Genomic_DNA.
DR EMBL; AL731537; CAI17115.1; -; Genomic_DNA.
DR EMBL; AL928686; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AL391378; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AL157399; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AC027118; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AC026228; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AC022537; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AC022025; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AC009986; CAI17115.1; JOINED; Genomic_DNA.
DR EMBL; AC068062; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC069079; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC073584; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL596105; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL607031; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471083; EAW54140.1; -; Genomic_DNA.
DR EMBL; BC062688; AAH62688.1; -; mRNA.
DR EMBL; BC127090; AAI27091.1; -; mRNA.
DR CCDS; CCDS44399.1; -. [Q13976-1]
DR CCDS; CCDS7244.1; -. [Q13976-2]
DR PIR; S05702; S05702.
DR RefSeq; NP_001091982.1; NM_001098512.2. [Q13976-1]
DR RefSeq; NP_006249.1; NM_006258.3. [Q13976-2]
DR PDB; 1ZXA; NMR; -; A/B=2-59.
DR PDB; 3NMD; X-ray; 2.27 A; A/B/C/D/E=4-47.
DR PDB; 3OCP; X-ray; 2.49 A; A/B=84-212.
DR PDB; 3OD0; X-ray; 2.90 A; A/B=84-212.
DR PDB; 3OGJ; X-ray; 2.75 A; A/B/C/D=84-212.
DR PDB; 4KU7; X-ray; 1.65 A; A=204-354.
DR PDB; 4KU8; X-ray; 1.99 A; A/B/C=204-354.
DR PDB; 4QX5; X-ray; 1.32 A; A=204-354.
DR PDB; 4QXK; Other; 2.20 A; A=204-354.
DR PDB; 4R4L; X-ray; 2.25 A; A/B/C=2-48.
DR PDB; 4R4M; X-ray; 1.92 A; A/B/C=2-48.
DR PDB; 4Z07; X-ray; 2.50 A; A/C/E=84-336.
DR PDB; 5J48; X-ray; 1.49 A; A/B=204-336.
DR PDB; 5JAX; X-ray; 1.49 A; A=204-336.
DR PDB; 5JD7; X-ray; 1.75 A; A=204-336.
DR PDB; 5L0N; X-ray; 1.28 A; A=204-336.
DR PDB; 6BDL; X-ray; 1.96 A; A/B=327-671.
DR PDB; 6BG2; X-ray; 1.83 A; A/B/C/D=327-671.
DR PDB; 6C0T; X-ray; 1.98 A; A=327-671.
DR PDBsum; 1ZXA; -.
DR PDBsum; 3NMD; -.
DR PDBsum; 3OCP; -.
DR PDBsum; 3OD0; -.
DR PDBsum; 3OGJ; -.
DR PDBsum; 4KU7; -.
DR PDBsum; 4KU8; -.
DR PDBsum; 4QX5; -.
DR PDBsum; 4QXK; -.
DR PDBsum; 4R4L; -.
DR PDBsum; 4R4M; -.
DR PDBsum; 4Z07; -.
DR PDBsum; 5J48; -.
DR PDBsum; 5JAX; -.
DR PDBsum; 5JD7; -.
DR PDBsum; 5L0N; -.
DR PDBsum; 6BDL; -.
DR PDBsum; 6BG2; -.
DR PDBsum; 6C0T; -.
DR AlphaFoldDB; Q13976; -.
DR BMRB; Q13976; -.
DR SMR; Q13976; -.
DR BioGRID; 111578; 35.
DR DIP; DIP-41118N; -.
DR DIP; DIP-46288N; -.
DR IntAct; Q13976; 26.
DR MINT; Q13976; -.
DR STRING; 9606.ENSP00000363092; -.
DR BindingDB; Q13976; -.
DR ChEMBL; CHEMBL4273; -.
DR DrugCentral; Q13976; -.
DR GuidetoPHARMACOLOGY; 1492; -.
DR GlyGen; Q13976; 1 site, 2 O-linked glycans (1 site).
DR iPTMnet; Q13976; -.
DR MetOSite; Q13976; -.
DR PhosphoSitePlus; Q13976; -.
DR BioMuta; PRKG1; -.
DR DMDM; 6225588; -.
DR EPD; Q13976; -.
DR jPOST; Q13976; -.
DR MassIVE; Q13976; -.
DR MaxQB; Q13976; -.
DR PeptideAtlas; Q13976; -.
DR PRIDE; Q13976; -.
DR ProteomicsDB; 59781; -. [Q13976-1]
DR ProteomicsDB; 59782; -. [Q13976-2]
DR Antibodypedia; 2108; 344 antibodies from 38 providers.
DR DNASU; 5592; -.
DR Ensembl; ENST00000373980.11; ENSP00000363092.5; ENSG00000185532.20. [Q13976-2]
DR Ensembl; ENST00000401604.8; ENSP00000384200.4; ENSG00000185532.20. [Q13976-1]
DR GeneID; 5592; -.
DR KEGG; hsa:5592; -.
DR MANE-Select; ENST00000373980.11; ENSP00000363092.5; NM_006258.4; NP_006249.1. [Q13976-2]
DR UCSC; uc001jjo.4; human. [Q13976-1]
DR CTD; 5592; -.
DR DisGeNET; 5592; -.
DR GeneCards; PRKG1; -.
DR HGNC; HGNC:9414; PRKG1.
DR HPA; ENSG00000185532; Tissue enhanced (tongue).
DR MalaCards; PRKG1; -.
DR MIM; 176894; gene.
DR MIM; 615436; phenotype.
DR neXtProt; NX_Q13976; -.
DR OpenTargets; ENSG00000185532; -.
DR Orphanet; 91387; Familial thoracic aortic aneurysm and aortic dissection.
DR PharmGKB; PA33777; -.
DR VEuPathDB; HostDB:ENSG00000185532; -.
DR eggNOG; KOG0614; Eukaryota.
DR GeneTree; ENSGT00940000154704; -.
DR HOGENOM; CLU_000288_73_2_1; -.
DR InParanoid; Q13976; -.
DR OMA; XTHYENG; -.
DR OrthoDB; 401933at2759; -.
DR PhylomeDB; Q13976; -.
DR TreeFam; TF313261; -.
DR BRENDA; 2.7.11.12; 2681.
DR PathwayCommons; Q13976; -.
DR Reactome; R-HSA-392517; Rap1 signalling. [Q13976-1]
DR Reactome; R-HSA-4086398; Ca2+ pathway.
DR Reactome; R-HSA-418457; cGMP effects. [Q13976-1]
DR SABIO-RK; Q13976; -.
DR SignaLink; Q13976; -.
DR SIGNOR; Q13976; -.
DR BioGRID-ORCS; 5592; 19 hits in 1110 CRISPR screens.
DR ChiTaRS; PRKG1; human.
DR EvolutionaryTrace; Q13976; -.
DR GeneWiki; PRKG1; -.
DR GenomeRNAi; 5592; -.
DR Pharos; Q13976; Tchem.
DR PRO; PR:Q13976; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; Q13976; protein.
DR Bgee; ENSG00000185532; Expressed in saphenous vein and 170 other tissues.
DR ExpressionAtlas; Q13976; baseline and differential.
DR Genevisible; Q13976; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005246; F:calcium channel regulator activity; IDA:UniProtKB.
DR GO; GO:0030553; F:cGMP binding; IEA:UniProtKB-KW.
DR GO; GO:0004692; F:cGMP-dependent protein kinase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0004672; F:protein kinase activity; IMP:BHF-UCL.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0030036; P:actin cytoskeleton organization; TAS:ProtInc.
DR GO; GO:0019934; P:cGMP-mediated signaling; IEA:Ensembl.
DR GO; GO:0016358; P:dendrite development; IEA:Ensembl.
DR GO; GO:0030900; P:forebrain development; IEA:Ensembl.
DR GO; GO:0090331; P:negative regulation of platelet aggregation; IMP:UniProtKB.
DR GO; GO:1904753; P:negative regulation of vascular associated smooth muscle cell migration; IDA:BHF-UCL.
DR GO; GO:1904706; P:negative regulation of vascular associated smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc.
DR GO; GO:0043087; P:regulation of GTPase activity; IMP:UniProtKB.
DR GO; GO:0060087; P:relaxation of vascular associated smooth muscle; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
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; PS00888; CNMP_BINDING_1; 2.
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 3D-structure; Acetylation; Allosteric enzyme; Alternative splicing;
KW Aortic aneurysm; ATP-binding; cGMP; cGMP-binding; Coiled coil; Cytoplasm;
KW Disease variant; Disulfide bond; Kinase; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase;
KW Transferase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22223895"
FT CHAIN 2..671
FT /note="cGMP-dependent protein kinase 1"
FT /id="PRO_0000086115"
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 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 REGION 221..341
FT /note="cGMP-binding, low affinity"
FT REGION 635..671
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 2..59
FT /evidence="ECO:0000269|PubMed:16131665"
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 AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21526164,
FT ECO:0007744|PDB:3OCP, ECO:0007744|PDB:3OGJ"
FT BINDING 167..170
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21526164,
FT ECO:0007744|PDB:3OD0"
FT BINDING 177..178
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21526164,
FT ECO:0007744|PDB:3OCP, ECO:0007744|PDB:3OGJ"
FT BINDING 177..178
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:21526164,
FT ECO:0007744|PDB:3OD0"
FT BINDING 282
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:24239458,
FT ECO:0000269|PubMed:25271401, ECO:0007744|PDB:4KU7,
FT ECO:0007744|PDB:4QXK"
FT BINDING 291..294
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25271401,
FT ECO:0007744|PDB:4QX5"
FT BINDING 291..294
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:24239458,
FT ECO:0000269|PubMed:25271401, ECO:0007744|PDB:4KU7,
FT ECO:0007744|PDB:4QXK"
FT BINDING 301..302
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25271401,
FT ECO:0007744|PDB:4QX5"
FT BINDING 301..302
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:24239458,
FT ECO:0000269|PubMed:25271401, ECO:0007744|PDB:4KU7,
FT ECO:0007744|PDB:4QXK"
FT BINDING 336
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:25271401,
FT ECO:0007744|PDB:4QX5"
FT BINDING 336
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:24239458,
FT ECO:0000269|PubMed:25271401, ECO:0007744|PDB:4KU7,
FT ECO:0007744|PDB:4QXK"
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:0007744|PubMed:22223895"
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 VAR_SEQ 1..89
FT /note="MSELEEDFAKILMLKEERIKELEKRLSEKEEEIQELKRKLHKCQSVLPVPST
FT HIGPRTTRAQGISAEPQTYRSFHDLRQAFRKFTKSER -> MGTLRDLQYALQEKIEEL
FT RQRDALIDELELELDQKDELIQKLQNELDKYRSVIRPATQQAQKQSASTLQGEPRTKRQ
FT AISAEPTAFDIQDLSHVTLPFYPKSPQ (in isoform Beta)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:17974005, ECO:0000303|PubMed:2792381"
FT /id="VSP_038714"
FT VAR_SEQ 1..15
FT /note="MSELEEDFAKILMLK -> MEKQNMFLHGSYILR (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055541"
FT VAR_SEQ 16..297
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055542"
FT VARIANT 177
FT /note="R -> Q (in AAT8; impairs cGMP binding; the mutant
FT protein is constitutively active; dbSNP:rs397515330)"
FT /evidence="ECO:0000269|PubMed:23910461"
FT /id="VAR_070434"
FT VARIANT 249
FT /note="I -> V (in dbSNP:rs56082459)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_046773"
FT VARIANT 267
FT /note="N -> S (in dbSNP:rs34997494)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_051632"
FT VARIANT 474
FT /note="Y -> F (in dbSNP:rs149710600)"
FT /evidence="ECO:0000269|PubMed:23910461"
FT /id="VAR_070435"
FT VARIANT 666
FT /note="G -> A (in dbSNP:rs750949508)"
FT /evidence="ECO:0000269|PubMed:23910461"
FT /id="VAR_070436"
FT MUTAGEN 12
FT /note="L->A: Loss of binding to PPP1R12A."
FT /evidence="ECO:0000269|PubMed:10567269"
FT MUTAGEN 19
FT /note="I->A: Loss of binding to PPP1R12A."
FT /evidence="ECO:0000269|PubMed:10567269"
FT MUTAGEN 26
FT /note="L->P: Loss of binding to PPP1R12A."
FT /evidence="ECO:0000269|PubMed:10567269"
FT MUTAGEN 33
FT /note="I->A: Loss of binding to PPP1R12A."
FT /evidence="ECO:0000269|PubMed:10567269"
FT MUTAGEN 40
FT /note="L->A: Loss of binding to PPP1R12A."
FT /evidence="ECO:0000269|PubMed:10567269"
FT MUTAGEN 281
FT /note="L->A: Reduces cGMP binding affinity."
FT /evidence="ECO:0000269|PubMed:24239458"
FT MUTAGEN 282
FT /note="R->A: Reduces cGMP binding affinity."
FT /evidence="ECO:0000269|PubMed:24239458"
FT MUTAGEN 302
FT /note="T->A: Reduces cGMP binding affinity."
FT /evidence="ECO:0000269|PubMed:24239458"
FT MUTAGEN 336
FT /note="Y->A: Reduces cGMP binding affinity."
FT /evidence="ECO:0000269|PubMed:24239458"
FT HELIX 3..44
FT /evidence="ECO:0007829|PDB:4R4M"
FT HELIX 88..100
FT /evidence="ECO:0007829|PDB:3OCP"
FT TURN 102..106
FT /evidence="ECO:0007829|PDB:3OCP"
FT HELIX 109..118
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 120..124
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 129..131
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 139..145
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 148..152
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 155..160
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 165..167
FT /evidence="ECO:0007829|PDB:3OCP"
FT HELIX 169..173
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 174..176
FT /evidence="ECO:0007829|PDB:3OD0"
FT STRAND 178..185
FT /evidence="ECO:0007829|PDB:3OCP"
FT STRAND 187..193
FT /evidence="ECO:0007829|PDB:3OCP"
FT HELIX 194..201
FT /evidence="ECO:0007829|PDB:3OCP"
FT HELIX 209..217
FT /evidence="ECO:0007829|PDB:5L0N"
FT HELIX 220..222
FT /evidence="ECO:0007829|PDB:5L0N"
FT HELIX 227..236
FT /evidence="ECO:0007829|PDB:5L0N"
FT STRAND 238..242
FT /evidence="ECO:0007829|PDB:5L0N"
FT STRAND 247..249
FT /evidence="ECO:0007829|PDB:5L0N"
FT STRAND 257..264
FT /evidence="ECO:0007829|PDB:5L0N"
FT STRAND 266..270
FT /evidence="ECO:0007829|PDB:5L0N"
FT STRAND 274..276
FT /evidence="ECO:0007829|PDB:4KU8"
FT STRAND 279..284
FT /evidence="ECO:0007829|PDB:5L0N"
FT HELIX 292..296
FT /evidence="ECO:0007829|PDB:5L0N"
FT STRAND 297..300
FT /evidence="ECO:0007829|PDB:4Z07"
FT STRAND 303..317
FT /evidence="ECO:0007829|PDB:5L0N"
FT HELIX 318..325
FT /evidence="ECO:0007829|PDB:5L0N"
FT TURN 326..329
FT /evidence="ECO:0007829|PDB:5L0N"
FT HELIX 339..353
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 357..359
FT /evidence="ECO:0007829|PDB:6BG2"
FT STRAND 360..368
FT /evidence="ECO:0007829|PDB:6BG2"
FT STRAND 373..379
FT /evidence="ECO:0007829|PDB:6BG2"
FT STRAND 386..393
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 394..399
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 403..415
FT /evidence="ECO:0007829|PDB:6BG2"
FT STRAND 424..429
FT /evidence="ECO:0007829|PDB:6BG2"
FT STRAND 431..439
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 446..453
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 458..477
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 487..489
FT /evidence="ECO:0007829|PDB:6BG2"
FT STRAND 490..492
FT /evidence="ECO:0007829|PDB:6BG2"
FT STRAND 498..500
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 522..524
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 527..530
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 538..553
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 563..572
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 574..576
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 585..594
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 599..601
FT /evidence="ECO:0007829|PDB:6BG2"
FT TURN 607..609
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 610..614
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 617..619
FT /evidence="ECO:0007829|PDB:6BG2"
FT HELIX 624..628
FT /evidence="ECO:0007829|PDB:6BG2"
FT TURN 667..670
FT /evidence="ECO:0007829|PDB:6BG2"
SQ SEQUENCE 671 AA; 76364 MW; 51389502A5E5FBD2 CRC64;
MSELEEDFAK ILMLKEERIK ELEKRLSEKE EEIQELKRKL HKCQSVLPVP STHIGPRTTR
AQGISAEPQT YRSFHDLRQA FRKFTKSERS KDLIKEAILD NDFMKNLELS QIQEIVDCMY
PVEYGKDSCI IKEGDVGSLV YVMEDGKVEV TKEGVKLCTM GPGKVFGELA ILYNCTRTAT
VKTLVNVKLW AIDRQCFQTI MMRTGLIKHT EYMEFLKSVP TFQSLPEEIL SKLADVLEET
HYENGEYIIR QGARGDTFFI ISKGTVNVTR EDSPSEDPVF 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 SFPEDNDEPP
PDDNSGWDID F
