KGP_PLABA
ID KGP_PLABA Reviewed; 856 AA.
AC A0A509AKL0;
DT 10-FEB-2021, integrated into UniProtKB/Swiss-Prot.
DT 18-SEP-2019, sequence version 1.
DT 03-AUG-2022, entry version 15.
DE RecName: Full=cGMP-dependent protein kinase {ECO:0000303|PubMed:19779564};
DE EC=2.7.11.12 {ECO:0000250|UniProtKB:Q8I719};
DE AltName: Full=PbPKG {ECO:0000303|PubMed:19940133};
GN Name=PKG {ECO:0000303|PubMed:19779564};
GN ORFNames=PBANKA_1008200 {ECO:0000312|EMBL:VUC56080.1};
OS Plasmodium berghei (strain Anka).
OC Eukaryota; Sar; Alveolata; Apicomplexa; Aconoidasida; Haemosporida;
OC Plasmodiidae; Plasmodium; Plasmodium (Vinckeia).
OX NCBI_TaxID=5823 {ECO:0000312|Proteomes:UP000074855};
RN [1] {ECO:0000312|Proteomes:UP000074855}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ANKA {ECO:0000312|Proteomes:UP000074855};
RX PubMed=25359557; DOI=10.1186/s12915-014-0086-0;
RA Otto T.D., Bohme U., Jackson A.P., Hunt M., Franke-Fayard B.,
RA Hoeijmakers W.A., Religa A.A., Robertson L., Sanders M., Ogun S.A.,
RA Cunningham D., Erhart A., Billker O., Khan S.M., Stunnenberg H.G.,
RA Langhorne J., Holder A.A., Waters A.P., Newbold C.I., Pain A., Berriman M.,
RA Janse C.J.;
RT "A comprehensive evaluation of rodent malaria parasite genomes and gene
RT expression.";
RL BMC Biol. 12:86-86(2014).
RN [2] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, AND DEVELOPMENTAL STAGE.
RX PubMed=19779564; DOI=10.1371/journal.ppat.1000599;
RA Moon R.W., Taylor C.J., Bex C., Schepers R., Goulding D., Janse C.J.,
RA Waters A.P., Baker D.A., Billker O.;
RT "A cyclic GMP signalling module that regulates gliding motility in a
RT malaria parasite.";
RL PLoS Pathog. 5:e1000599-e1000599(2009).
RN [3] {ECO:0000305}
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=19940133; DOI=10.1074/jbc.m109.070367;
RA Falae A., Combe A., Amaladoss A., Carvalho T., Menard R., Bhanot P.;
RT "Role of Plasmodium berghei cGMP-dependent protein kinase in late liver
RT stage development.";
RL J. Biol. Chem. 285:3282-3288(2010).
RN [4] {ECO:0000305}
RP FUNCTION, AND MUTAGENESIS OF THR-622.
RX PubMed=24594931; DOI=10.1371/journal.pbio.1001806;
RA Brochet M., Collins M.O., Smith T.K., Thompson E., Sebastian S.,
RA Volkmann K., Schwach F., Chappell L., Gomes A.R., Berriman M., Rayner J.C.,
RA Baker D.A., Choudhary J., Billker O.;
RT "Phosphoinositide metabolism links cGMP-dependent protein kinase G to
RT essential Ca(2+) signals at key decision points in the life cycle of
RT malaria parasites.";
RL PLoS Biol. 12:e1001806-e1001806(2014).
RN [5] {ECO:0000305}
RP FUNCTION, SUBCELLULAR LOCATION, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE,
RP AND MUTAGENESIS OF THR-622.
RX PubMed=27425827; DOI=10.1111/mmi.13466;
RA Govindasamy K., Jebiwott S., Jaijyan D.K., Davidow A., Ojo K.K.,
RA Van Voorhis W.C., Brochet M., Billker O., Bhanot P.;
RT "Invasion of hepatocytes by Plasmodium sporozoites requires cGMP-dependent
RT protein kinase and calcium dependent protein kinase 4.";
RL Mol. Microbiol. 102:349-363(2016).
RN [6] {ECO:0000305}
RP FUNCTION, AND MUTAGENESIS OF THR-622.
RX PubMed=30315162; DOI=10.1038/s41467-018-06733-w;
RA Fang H., Gomes A.R., Klages N., Pino P., Maco B., Walker E.M.,
RA Zenonos Z.A., Angrisano F., Baum J., Doerig C., Baker D.A., Billker O.,
RA Brochet M.;
RT "Epistasis studies reveal redundancy among calcium-dependent protein
RT kinases in motility and invasion of malaria parasites.";
RL Nat. Commun. 9:4248-4248(2018).
CC -!- FUNCTION: Serine/threonine protein kinase which acts as a downstream
CC effector of the second messenger cGMP (By similarity). Controls the
CC release of Ca(2+) from intracellular stores by regulating
CC phosphoinositide biosynthesis (PubMed:24594931). Ca(2+) signals are
CC essential for merozoite and sporozoite invasion and egress from host
CC hepatocytes and erythrocytes, and, in the mosquito vector, for
CC gametocyte activation, and ookinete and sporozoite motility
CC (PubMed:24594931). During the host liver stage, regulates the initial
CC invasion of host hepatocytes by sporozoites by regulating sporozoite
CC motility and microneme exocytosis (PubMed:27425827). Following parasite
CC development in the hepatocytes, required for the release of merosomes,
CC a vesicle containing the mature merozoites (PubMed:19940133,
CC PubMed:27425827). 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 (By similarity).
CC Regulates merozoite egress by promoting the release of exonemes and
CC micronemes which contain proteins essential for egress (By similarity).
CC Phosphorylates CDPK1 predominantly at the late schizont stage;
CC phosphorylation at 'Ser-64' regulates CDPK1 protein-protein interaction
CC and phosphorylation at 'Thr-231' may regulate CDPK1 kinase activity (By
CC similarity). In the mosquito vector, required for the initiation of
CC gametogenesis induced by xanthurenic acid, specifically the gametocyte
CC differentiation from the crescent-shaped form to the spherical form
CC (PubMed:24594931). Required for the gliding motility of ookinetes to
CC reach and penetrate the midgut epithelium by promoting Ca(2+)-mediated
CC activation of CDPK1 and CDPK4 (PubMed:19779564, PubMed:24594931,
CC PubMed:30315162). Also required for microneme secretion in ookinete by
CC promoting Ca(2+)-mediated activation of CDPK3 (PubMed:30315162).
CC {ECO:0000250|UniProtKB:Q8I719, ECO:0000269|PubMed:19779564,
CC ECO:0000269|PubMed:19940133, ECO:0000269|PubMed:24594931,
CC ECO:0000269|PubMed:27425827, ECO:0000269|PubMed:30315162}.
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:0000250|UniProtKB:Q8I719};
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:0000250|UniProtKB:Q8I719};
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-488, Gln-
CC 536 and Asp-537, 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:0000269|PubMed:19779564,
CC ECO:0000269|PubMed:27425827}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q8I719}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q8I719}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:Q8I719}. Note=Predominantly localizes to the
CC cytoplasm during schizogony. {ECO:0000250|UniProtKB:Q8I719}.
CC -!- DEVELOPMENTAL STAGE: Expressed during the parasite blood stage
CC including gametocytes (PubMed:19779564). Expressed in sporozoites (at
CC protein level) (PubMed:27425827). Expressed during the parasite liver
CC stages (at protein level) (PubMed:19940133, PubMed:27425827). In the
CC mosquito host, expressed in the ookinetes (PubMed:19779564).
CC {ECO:0000269|PubMed:19779564, ECO:0000269|PubMed:19940133,
CC ECO:0000269|PubMed:27425827}.
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 -!- DISRUPTION PHENOTYPE: Knockout sporozoites can infect their mouse host,
CC however they fail to develop into erythrocyte stage parasite due to
CC impaired late liver stage development (PubMed:19940133). Sporozoites
CC invasion of hepatocytes is normal due to residual expression of PKG
CC (PubMed:27425827). During the liver stage, the development of
CC merozoites is normal but the release of merosomes, a vesicle containing
CC the mature merozoites, is impaired (PubMed:19940133).
CC {ECO:0000269|PubMed:19940133, ECO:0000269|PubMed:27425827}.
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; LK023125; VUC56080.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A509AKL0; -.
DR SMR; A0A509AKL0; -.
DR STRING; 5823.A0A509AKL0; -.
DR VEuPathDB; PlasmoDB:PBANKA_1008200; -.
DR OMA; SKNPDGH; -.
DR Proteomes; UP000074855; Chromosome 10.
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; IEA:UniProtKB-EC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006468; P:protein phosphorylation; IEA:InterPro.
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; 3.
DR PROSITE; PS00889; CNMP_BINDING_2; 3.
DR PROSITE; PS50042; CNMP_BINDING_3; 4.
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..856
FT /note="cGMP-dependent protein kinase"
FT /id="PRO_0000451910"
FT DOMAIN 545..802
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 803..856
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT REGION 1..33
FT /note="Autoinhibitory segment"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT REGION 62..177
FT /note="cNMP-binding domain 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 180..279
FT /note="cNMP-binding domain 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 299..402
FT /note="cNMP-binding domain 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 422..521
FT /note="cNMP-binding domain 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00060"
FT REGION 837..856
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 841..856
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 668
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 117
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 126
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 127
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 129
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 136
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 137
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 477
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 486
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 487
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 489
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 496
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 497
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 551..559
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 574
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 488
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 536
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 537
FT /note="Part of a catalytic triad required for cGMP binding
FT and cGMP-dependent kinase activity"
FT /evidence="ECO:0000250|UniProtKB:Q8I719"
FT MUTAGEN 622
FT /note="T->Q: Reduces intracellular Ca(2+) increase in
FT response to cGMP during early gametogenesis. Normal asexual
FT growth rate, gametocyte and ookinete formation, midgut
FT oocyst numbers, salivary gland sporozoite numbers, and
FT sporozoite infectivity to mice. In a CDPK4 knockout
FT background, reduces ring formation and thus the number of
FT schizonts in infected mice. In addition, merozoites have a
FT discontinuous inner membrane complex. Also, male
FT gametocytes fail to exflagellate in the mosquito vector.
FT Resistant to trisubstituted pyrrole compound 1 (C1) and
FT imidazopyridine-based compound 2 (C2) inhibitors."
FT /evidence="ECO:0000269|PubMed:24594931,
FT ECO:0000269|PubMed:30315162"
SQ SEQUENCE 856 AA; 97901 MW; 5523ACE4F121799D CRC64;
MDDDEIIPKK NHPSNERNKK KAILSHEDFT GEDSLMENHL ELRDKLTEDI VTIKASLKNN
LVCSTLNENE ILALSNYMQF FVFKSGDMVI KQGEKGSYFF IINSGKFDVY VNDKKVKTLT
KGSSFGEAAL IHNTQRSATI KAGTNGTLWG VQRSTFRATL KQLSNRNFNE NRSFIDSVSV
FDMLTEAQKN MITNACVIQN FKPGETIVKQ GDYGDVLYIL KDGKATVYIN DEEIRVLEKG
SYFGERALLY DEPRSATIIA KEVTSCASIC RKLLNVVLGN LQVVLFRNIM TEALQQSEIF
KQISPDQLND LADTAIVRDY PANYNILHKD KIKSVKYIIV LEGKVELFLD DESIGILTRG
KSFGDQYVLN QKQKFKHTLK SLEVCKIALI TESCLADCLG NNNIDASIDY NNKKSIIKKM
YIFRYLTDKQ CNLLIEAFKT TRYEEGDYII QEGEVGSRFY IIKAGEVEIV KNNKRLRTLG
KNDYFGERAL IYDEPRTASV ISTVNNLECW YVDKSVFLQI IEGPMLAHLE ERIKMQDTKV
EMSELLTERI IGRGTFGIVK LVLHEPTKIR YALKCVSKKS IIELNQQNNI KLEREITAEN
DHPFIIRLVR TFKDSKYFYF LTELVTGGEL YDAIRKLGLL SRSQAQFYLG SIILAIEYLH
ERSIVYRDLK PENILLDKQG YVKLIDFGCA KKIHGRSYTL VGTPHYMAPE VILGKGYGCT
VDIWAFGVCL YEFICGPLPF GNDQEDQLEI FRDILTGQLT FPDYVTDTDS INLIKRLLCR
LPQGRIGCSI NGFKDIKENS FFADFDWDRL AGRLLEPPLI SKSETYAEDI DVKQIEQEEE
DNANTEIDDE NWDIDF
