KGP_PLAFO
ID KGP_PLAFO Reviewed; 853 AA.
AC W7JX98; Q8MMZ4;
DT 10-FEB-2021, integrated into UniProtKB/Swiss-Prot.
DT 10-FEB-2021, sequence version 2.
DT 03-AUG-2022, entry version 47.
DE RecName: Full=cGMP-dependent protein kinase {ECO:0000303|PubMed:16325279};
DE EC=2.7.11.12 {ECO:0000269|PubMed:16325279};
GN Name=PKG {ECO:0000303|PubMed:16325279};
GN ORFNames=PFNF54_05395 {ECO:0000312|EMBL:EWC85729.1};
OS Plasmodium falciparum (isolate NF54).
OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida;
OC Plasmodiidae; Plasmodium; Plasmodium (Laverania).
OX NCBI_TaxID=5843 {ECO:0000312|Proteomes:UP000030673};
RN [1] {ECO:0000312|EMBL:AAM22644.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11834729; DOI=10.1074/jbc.m108393200;
RA Gurnett A., Liberator P.A., Dulski P., Salowe S.P., Donald R.G.K.,
RA Anderson J.W., Wiltsie J., Diaz-Saldana C.A., Harris G., Chang B.,
RA Darkin-Rattray S.J., Nare B., Crumley T., Blum P., Misura A., Tamas T.,
RA Sardana M., Yuan J., Biftu T., Schmatz D.;
RT "Purification and molecular characterization of cGMP-dependent protein
RT kinase from Apicomplexan parasites. A novel chemotherapeutic target.";
RL J. Biol. Chem. 277:15913-15922(2002).
RN [2] {ECO:0000312|EMBL:AAM22644.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, AND DEVELOPMENTAL
RP STAGE.
RX PubMed=16325279; DOI=10.1016/j.molbiopara.2005.10.020;
RA Diaz C.A., Allocco J., Powles M.A., Yeung L., Donald R.G., Anderson J.W.,
RA Liberator P.A.;
RT "Characterization of Plasmodium falciparum cGMP-dependent protein kinase
RT (PfPKG): antiparasitic activity of a PKG inhibitor.";
RL Mol. Biochem. Parasitol. 146:78-88(2006).
RN [3] {ECO:0000312|Proteomes:UP000030673}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=NF54 {ECO:0000312|Proteomes:UP000030673};
RG The Broad Institute Genome Sequencing Platform;
RG The Broad Institute Genome Sequencing Center for Infectious Disease;
RA Neafsey D., Cheeseman I., Volkman S., Adams J., Walker B., Young S.K.,
RA Zeng Q., Gargeya S., Fitzgerald M., Haas B., Abouelleil A., Alvarado L.,
RA Arachchi H.M., Berlin A.M., Chapman S.B., Dewar J., Goldberg J., Griggs A.,
RA Gujja S., Hansen M., Howarth C., Imamovic A., Larimer J., McCowan C.,
RA Murphy C., Neiman D., Pearson M., Priest M., Roberts A., Saif S., Shea T.,
RA Sisk P., Sykes S., Wortman J., Nusbaum C., Birren B.;
RT "The Genome Sequence of Plasmodium falciparum NF54.";
RL Submitted (FEB-2013) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Serine/threonine protein kinase which acts as a downstream
CC effector of the second messenger cGMP (PubMed:16325279). Controls the
CC release of Ca(2+) from intracellular stores by regulating
CC phosphoinositide biosynthesis. Ca(2+) signals are essential for
CC merozoite and sporozoite invasion and egress from host hepatocytes and
CC erythrocytes, and, in the mosquito vector, for gametocyte activation,
CC and ookinete and sporozoite motility (By similarity). During the host
CC liver stage, regulates the initial invasion of host hepatocytes by
CC sporozoites by regulating sporozoite motility and microneme exocytosis.
CC Following parasite development in the hepatocytes, required for the
CC release of merosomes, a vesicle containing the mature merozoites (By
CC similarity). During the asexual blood stage, required for the
CC progression from schizont to the ring stage following merozoite
CC invasion of host erythrocytes and for merozoite egress. Regulates
CC merozoite egress by promoting the release of exonemes and micronemes
CC which contain proteins essential for egress. Phosphorylates CDPK1
CC predominantly at the late schizont stage; phosphorylation at 'Ser-64'
CC regulates CDPK1 protein-protein interaction and phosphorylation at
CC 'Thr-231' may regulate CDPK1 kinase activity. In the mosquito vector,
CC required for the initiation of gametogenesis induced by xanthurenic
CC acid, specifically the gametocyte differentiation from the crescent-
CC shaped form to the spherical form (By similarity). Required for the
CC gliding motility of ookinetes to reach and penetrate the midgut
CC epithelium by promoting Ca(2+)-mediated activation of CDPK1 and CDPK4.
CC Also required for microneme secretion in ookinete by promoting Ca(2+)-
CC mediated activation of CDPK3 (By similarity).
CC {ECO:0000250|UniProtKB:A0A509AKL0, ECO:0000250|UniProtKB:Q8I719,
CC ECO:0000269|PubMed:16325279}.
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 Evidence={ECO:0000269|PubMed:16325279};
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; Evidence={ECO:0000269|PubMed:16325279};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q8I719};
CC -!- ACTIVITY REGULATION: Activated by cGMP. Not activated by cAMP. cGMP
CC binding allosterically triggers a conformational change at the alpha C-
CC helix of cGMP-binding domain 4, which bridges the regulatory and
CC catalytic domains, causing the capping triad, composed of Arg-484, Gln-
CC 532 and Asp-533, to form and stabilize the active conformation. The
CC cGMP-binding domains acts cooperatively to activate PKG.
CC {ECO:0000250|UniProtKB:Q8I719}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:Q8I719}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q8I719}.
CC Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q8I719};
CC Peripheral membrane protein {ECO:0000250|UniProtKB:Q8I719}; Cytoplasmic
CC side {ECO:0000250|UniProtKB:Q8I719}. Note=Predominantly localizes to
CC the cytoplasm during schizogony. {ECO:0000250|UniProtKB:Q8I719}.
CC -!- DEVELOPMENTAL STAGE: During the parasite blood stage, highly expressed
CC at the ring stage and in gametocytes (PubMed:16325279). Low expression
CC in trophozoites (PubMed:16325279). {ECO:0000269|PubMed:16325279}.
CC -!- DOMAIN: The cNMP-binding domains 1, 2 and 4 bind preferentially cGMP.
CC The cNMP-binding domain 4 binds cGMP with the highest affinity and is
CC highly selective for cGMP. The cNMP-binding domain 3 does not bind cGMP
CC but is required for cGMP-dependent catalytic activity. The cNMP-binding
CC domains 1, 2 and 4 can bind cAMP but with less affinity.
CC {ECO:0000250|UniProtKB:Q8I719}.
CC -!- DOMAIN: The autoinhibitory segment (AIS) interacts with the active site
CC and inhibits catalytic activity. {ECO:0000250|UniProtKB:Q8I719}.
CC -!- PTM: Autophosphorylated. {ECO:0000250|UniProtKB:Q8I719}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. cGMP subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=EWC85729.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF465544; AAM22644.1; -; mRNA.
DR EMBL; KE123882; EWC85729.1; ALT_INIT; Genomic_DNA.
DR AlphaFoldDB; W7JX98; -.
DR SMR; W7JX98; -.
DR ChEMBL; CHEMBL2169724; -.
DR PRIDE; W7JX98; -.
DR EnsemblProtists; EWC85729; EWC85729; PFNF54_05395.
DR VEuPathDB; PlasmoDB:PF3D7_1436600; -.
DR VEuPathDB; PlasmoDB:Pf7G8_140041800; -.
DR VEuPathDB; PlasmoDB:PfCD01_140042000; -.
DR VEuPathDB; PlasmoDB:PfDd2_140041000; -.
DR VEuPathDB; PlasmoDB:PfGA01_140042100; -.
DR VEuPathDB; PlasmoDB:PfGB4_140042700; -.
DR VEuPathDB; PlasmoDB:PfGN01_140041900; -.
DR VEuPathDB; PlasmoDB:PfHB3_140042300; -.
DR VEuPathDB; PlasmoDB:PfIT_140043000; -.
DR VEuPathDB; PlasmoDB:PfKE01_140041500; -.
DR VEuPathDB; PlasmoDB:PfKH01_140042100; -.
DR VEuPathDB; PlasmoDB:PfKH02_140042300; -.
DR VEuPathDB; PlasmoDB:PfML01_140042100; -.
DR VEuPathDB; PlasmoDB:PfNF54_140040400; -.
DR VEuPathDB; PlasmoDB:PfSD01_140039900; -.
DR VEuPathDB; PlasmoDB:PfSN01_140043800; -.
DR VEuPathDB; PlasmoDB:PfTG01_140041900; -.
DR Proteomes; UP000030673; Unassembled WGS sequence.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
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:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR CDD; cd00038; CAP_ED; 4.
DR CDD; cd05572; STKc_cGK; 1.
DR Gene3D; 2.60.120.10; -; 4.
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; 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; 3.
DR Pfam; PF00069; Pkinase; 1.
DR PIRSF; PIRSF000559; cGMP-dep_kinase; 1.
DR SMART; SM00100; cNMP; 4.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF51206; SSF51206; 4.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS00888; CNMP_BINDING_1; 1.
DR PROSITE; PS00889; CNMP_BINDING_2; 1.
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 ATP-binding; cGMP; cGMP-binding; Cytoplasm; Endoplasmic reticulum; Kinase;
KW Magnesium; Membrane; Metal-binding; Nucleotide-binding; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..853
FT /note="cGMP-dependent protein kinase"
FT /id="PRO_0000451911"
FT DOMAIN 541..798
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 799..853
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT REGION 1..29
FT /note="Autoinhibitory segment"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT REGION 58..173
FT /note="cNMP-binding domain 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 176..275
FT /note="cNMP-binding domain 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 295..398
FT /note="cNMP-binding domain 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 418..517
FT /note="cNMP-binding domain 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 827..853
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 664
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 113
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 122
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 123
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 125
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 132
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 133
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="1"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 473
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 482
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 483
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 485
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 492
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 493
FT /ligand="3',5'-cyclic GMP"
FT /ligand_id="ChEBI:CHEBI:57746"
FT /ligand_label="2"
FT /ligand_note="allosteric activator"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT BINDING 547..555
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 570
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 484
FT /note="Part of a catalytic triad required for cGMP binding
FT and cGMP-dependent kinase activity"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT SITE 532
FT /note="Part of a catalytic triad required for cGMP binding
FT and cGMP-dependent kinase activity"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT SITE 533
FT /note="Part of a catalytic triad required for cGMP binding
FT and cGMP-dependent kinase activity"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
SQ SEQUENCE 853 AA; 97694 MW; DBBB189707A480E2 CRC64;
MEEDDNLKKG NERNKKKAIF SNDDFTGEDS LMEDHLELRE KLSEDIDMIK TSLKNNLVCS
TLNDNEILTL SNYMQFFVFK SGNLVIKQGE KGSYFFIINS GKFDVYVNDK KVKTMGKGSS
FGEAALIHNT QRSATIIAET DGTLWGVQRS TFRATLKQLS NRNFNENRTF IDSVSVFDML
TEAQKNMITN ACVIQNFKSG ETIVKQGDYG DVLYILKEGK ATVYINDEEI RVLEKGSYFG
ERALLYDEPR SATIIAKEPT ACASICRKLL NIVLGNLQVV LFRNIMTEAL QQSEIFKQFS
GDQLNDLADT AIVRDYPANY NILHKDKVKS VKYIIVLEGK VELFLDDTSI GILSRGMSFG
DQYVLNQKQP FKHTIKSLEV CKIALITETC LADCLGNNNI DASIDYNNKK SIIKKMYIFR
YLTDKQCNLL IEAFRTTRYE EGDYIIQEGE VGSRFYIIKN GEVEIVKNKK RLRTLGKNDY
FGERALLYDE PRTASVISKV NNVECWFVDK SVFLQIIQGP MLAHLEERIK MQDTKVEMDE
LETERIIGRG TFGTVKLVHH KPTKIRYALK CVSKRSIINL NQQNNIKLER EITAENDHPF
IIRLVRTFKD SKYFYFLTEL VTGGELYDAI RKLGLLSKSQ AQFYLGSIIL AIEYLHERNI
VYRDLKPENI LLDKQGYVKL IDFGCAKKVQ GRAYTLVGTP HYMAPEVILG KGYGCTVDIW
ALGICLYEFI CGPLPFGNDE EDQLEIFRDI LTGQLTFPDY VTDTDSINLM KRLLCRLPQG
RIGCSINGFK DIKDHPFFSN FNWDKLAGRL LDPPLVSKSE TYAEDIDIKQ IEEEDAEDDE
EPLNDEDNWD IDF
