{"gene":"PF3D7_1414400","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2002,"finding":"PF3D7_1414400 (PP1) encodes a 304-amino acid serine/threonine phosphatase with potent phosphatase activity in vitro; sensitivity to PP1-class inhibitors (e.g., calyculin A) and mutational analysis of catalytic residues confirmed its enzymatic mechanism; siRNA knockdown of PP1 inhibited parasite DNA synthesis, establishing an essential role in intraerythrocytic replication.","method":"Recombinant protein phosphatase assay, inhibitor sensitivity profiling, active-site mutagenesis, siRNA knockdown with DNA synthesis readout","journal":"Malaria journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic reconstitution with mutagenesis, inhibitor profiling, and functional siRNA knockdown in parasite; multiple orthogonal methods in one study","pmids":["12057017"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2002,"finding":"PF3D7_1414400 (PP1) functionally complements the glc7 (PP1) mutant of Saccharomyces cerevisiae, rescuing the low-glycogen phenotype, demonstrating conserved catalytic function and interaction with yeast proteins of the glycogen metabolism pathway; calyculin A (but not okadaic acid) caused hyperphosphorylation of a 51 kDa parasite protein, indicating predominant PP1 (over PP2A) activity in intraerythrocytic parasites.","method":"Yeast complementation assay (glc7 mutant rescue), phosphatase inhibitor treatment with phosphoprotein detection","journal":"International journal for parasitology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — heterologous complementation with functional readout, supported by inhibitor pharmacology; single lab but two orthogonal methods","pmids":["12062492"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"PF3D7_1414400 (PP1) is exported to the Maurer's clefts in the host erythrocyte cytoplasm, where it modulates the phosphorylation status of the amino-terminal domain of PfSBP1 (a trans-membrane Maurer's cleft protein); co-immunoprecipitation confirmed the PP1–PfSBP1 interaction; inhibition of PP1 with calyculin A caused hyperphosphorylation of PfSBP1 and blocked merozoite release, demonstrating that PP1 activity in the Maurer's clefts is required for parasite egress.","method":"Subcellular fractionation/immunolocalization, co-immunoprecipitation, calyculin A inhibition with phosphorylation and egress readouts","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, direct localization experiment tied to functional consequence (egress block), multiple orthogonal approaches in single lab","pmids":["16548885"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"PF3D7_1414400 (PP1) interacts with PfLRR1 (the P. falciparum Sds22 orthologue) as shown by GST pull-down and co-immunoprecipitation from parasite extracts; PfLRR1 inhibits PP1 phosphatase activity; in Xenopus oocytes PfLRR1 overcame the G2/M checkpoint to promote germinal vesicle breakdown (GVBD), mirroring effects of anti-PP1 antibodies or okadaic acid, placing PP1 regulation by PfLRR1 in cell cycle control.","method":"GST pull-down, co-immunoprecipitation from parasite lysate, in vitro phosphatase activity assay, Xenopus oocyte GVBD functional assay","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro binding + activity assay + heterologous functional rescue, multiple orthogonal methods, single lab","pmids":["16629662"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"PF3D7_1414400 (PP1) binds PfI3 (a P. falciparum Inhibitor-3 homolog) with high affinity (apparent KD ~100 nM) via the conserved KVVRW motif (Trp45 critical); unlike yeast/human I3, PfI3 increases PP1 phosphatase activity in vitro; PfI3 localizes to the nucleus of all blood-stage parasites (GFP tagging) and is essential for blood-stage survival (no viable knockouts obtained).","method":"NMR (structural characterization of PfI3), in vitro binding assays (multiple methods), in vitro phosphatase activity assay, site-directed mutagenesis (W45A), GFP localization, reverse genetics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR, in vitro reconstitution with mutagenesis, activity assay, and localization; single lab but multiple orthogonal methods","pmids":["22128182"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"PF3D7_1414400 (PP1) interacts with PfI2 (P. falciparum Inhibitor-2) via RVxF and HYNE motifs; both motifs are critical for binding and inhibition of PP1 phosphatase activity; PfI2 can overcome the G2/M checkpoint in Xenopus oocytes (GVBD), and peptides from PfI2 competing with RVxF binding sites in PP1 show antiplasmodial activity against blood-stage parasites in vitro.","method":"Biochemical interaction assays, in vitro phosphatase activity assay, site-directed mutagenesis of PfI2 motifs, Xenopus oocyte GVBD assay, antiplasmodial peptide assay","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with mutagenesis, functional heterologous assay, and antiplasmodial validation; multiple orthogonal methods, single lab","pmids":["23837822"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"PF3D7_1414400 (PP1) engages PfI2 through a two-site interaction: the canonical RVxF motif and a second FxxR/KxR/K motif (residues D94–T117); NMR spectroscopy identified the second site; mutation of either motif alone prevented PfI2-triggered GVBD in Xenopus oocytes, while only combined mutations abolished PP1 binding, showing that tight two-site association is necessary for PP1 regulation; a penetrating peptide derived from the FxxR/KxR/K motif accumulated specifically in infected erythrocytes and displayed antiplasmodial activity.","method":"NMR spectroscopy, site-directed mutagenesis of both binding motifs, Xenopus oocyte GVBD functional assay, antiplasmodial peptide assay with infected erythrocyte accumulation","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural definition, mutagenesis of both interaction sites, functional validation in heterologous model; single lab, multiple orthogonal methods","pmids":["25132288"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"finding":"PF3D7_1414400 (PP1) directly interacts with PfeIF2β (eukaryotic translation initiation factor 2β) via two binding motifs (FGEKKK and KVAW); both motifs are required for PP1 binding and for inducing GVBD in Xenopus oocytes; PP1 and PfeIF2β co-localize in cytoplasm and nuclear fractions of P. falciparum, suggesting regulation of PP1 in both compartments; attempts to knock out PfeIF2β were unsuccessful, indicating its essential role.","method":"In vitro interaction assay, site-directed mutagenesis of PfeIF2β binding motifs, Xenopus oocyte GVBD assay, subcellular fractionation, reverse genetics","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction with mutagenesis and functional Xenopus assay; localization by fractionation; single lab","pmids":["27303372"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"PF3D7_1414400 (PP1) directly interacts with PfRCC-PIP in vitro and forms a complex with it in the parasite; in Xenopus oocytes, RCC-PIP interacts with endogenous PP1 and acts in synergy with suboptimal progesterone to trigger oocyte maturation, suggesting a regulatory (activating) effect on PP1; RCC-PIP also interacts with the parasite kinase CDPK7 via its RCC1 motifs, indicating it is a dual kinase/phosphatase anchoring protein.","method":"In vitro pull-down, co-immunoprecipitation from parasite extracts, Xenopus oocyte maturation assay, reverse genetics","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding assay and functional heterologous assay; single lab, multiple methods","pmids":["30429842"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"PF3D7_1414400 (PP1) interacts with the pseudokinase PfpTKL via its SAM/RVxF motif; PP1 catalytic activity in Xenopus oocytes is modulated in an RVxF-dependent manner by pTKL, suggesting a scaffolding/regulatory role for pTKL toward PP1.","method":"In vitro interaction assay (SAM and RVxF motif mapping), Xenopus oocyte PP1 activity assay, reverse genetics in P. berghei","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding motif mapping and heterologous functional assay; single lab","pmids":["31148576"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"In P. berghei, PP1 (orthologue of PF3D7_1414400) interacts with GEXP15 via the RVxF binding motif; GEXP15 increases PP1 phosphatase activity in vitro; mutation of the RVxF motif abolishes this regulatory effect; immunoprecipitation with mass spectrometry confirmed the PP1–GEXP15 complex in both schizont and gametocyte stages, with associated proteins linked to spliceosome and proteasome pathways.","method":"In vitro interaction assay (RVxF mutagenesis), in vitro phosphatase activity assay, co-immunoprecipitation with mass spectrometry, phenotypic analysis of GEXP15-deficient P. berghei","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution with mutagenesis, activity assay, Co-IP/MS from parasite; replicated in P. falciparum context (PMID 37628837)","pmids":["31348803"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2020,"finding":"PF3D7_1414400 (PP1) is absolutely essential for egress of P. falciparum merozoites from host erythrocytes (but only required for efficient replication); phosphoproteomic and chemical-genetic analysis identified two direct functional targets of PP1 for egress: a HECT E3 ubiquitin ligase and GCα (a fusion guanylyl cyclase/phospholipid transporter); phosphatidylcholine stimulates PP1-dependent egress, implicating PP1 in lipid sensing via GCα.","method":"Conditional knockdown (chemical-genetic), phosphoproteomics, chemical-genetic epistasis analysis, phosphatidylcholine stimulation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — chemical-genetic conditional knockdown combined with phosphoproteomics and epistasis analysis; multiple orthogonal methods identifying pathway targets","pmids":["32669539"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"PP1 (P. berghei orthologue of PF3D7_1414400) is required for mitotic exit during rapid male gamete formation and potentially for establishing cell polarity during zygote development in the mosquito midgut; conditional knockdown combined with live-cell imaging, RNA-seq, and proteomics showed these roles in sexual/mosquito stages.","method":"Conditional gene knockdown, real-time live-cell imaging, ultrastructural imaging, RNA-seq, proteomics","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KD with defined cellular phenotypes (mitotic exit, cell polarity) and multiple orthogonal readouts; single lab","pmids":["34145386"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2022,"finding":"In P. berghei, PP1 (orthologue of PF3D7_1414400) forms a complex with PbLRR1 (Sds22 orthologue) in both asexual and sexual stages; PbLRR1 inhibits PP1 phosphatase activity; LRR1 depletion adversely affects oocyst development; phosphoproteomic analysis showed that Inhibitor-3 (I3) is drastically hypophosphorylated in LRR1-depleted parasites, suggesting that the phosphorylation status of I3 is controlled by the PP1–LRR1 complex.","method":"Co-immunoprecipitation from parasite extracts, in vitro phosphatase activity assay, genetic depletion of PbLRR1, interactome/phosphoproteomics","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro activity assay, Co-IP from native parasite, phosphoproteomics with genetic depletion; single lab, multiple orthogonal methods","pmids":["35920043"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2022,"finding":"PF3D7_1414400 (PP1) interactome mapped by mCherry-affinity pulldown followed by mass spectrometry in P. berghei asexual and sexual stages; PP1c-associated proteins are enriched in cellular component assembly (both stages), biosynthetic processes/translation (schizonts), and protein transport (gametocytes); nuclear export mediator factor and peptidyl-prolyl cis-trans isomerase were identified as potential targets of the PP1c/I2 complex in both stages.","method":"mCherry affinity pulldown from transgenic P. berghei, mass spectrometry interactome mapping","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown/MS interactome; single lab, single method for each identified partner","pmids":["35162991"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2023,"finding":"PF3D7_1414400 (PP1) directly interacts with GEXP15 in P. falciparum via the RVxF binding motif; this interaction enhances PP1 phosphatase activity; GEXP15 localizes predominantly to the nucleus in late asexual stages (live microscopy of tagged line); immunoprecipitation/mass spectrometry identified GEXP15 interaction with ribosomal and RNA-binding proteins, and pull-down of GEXP15 domains confirmed binding to the ribosomal complex via the GYF domain.","method":"In vitro interaction assay (RVxF mutagenesis), in vitro phosphatase activity assay, live microscopy of GFP/mCherry-tagged line, co-immunoprecipitation with mass spectrometry, recombinant domain pull-down","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with mutagenesis, activity assay, localization, and Co-IP/MS; single lab, multiple orthogonal methods","pmids":["37628837"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PF3D7_1414400 (PP1) controls the initiation of egress by regulating rounding-up of the parasitophorous vacuole, a step that is almost completely abolished in PP1-null schizonts; PP1 acts upstream of the cGMP-PKG signaling pathway by modulating basal guanylyl cyclase alpha (GCα) activity, thus controlling cGMP homeostasis and PKG-dependent Ca2+ signaling; the calcium ionophore A23187 bypasses the PP1-null egress defect, demonstrating Ca2+-dependence of rounding-up downstream of PP1.","method":"Conditional PP1 inducible knockout (iKO), fluorescent reporters of parasitophorous vacuole morphology, live microscopy of egress kinetics, chemical rescue with egress inducers and Ca2+ ionophore","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with live-imaging morphological readout, epistasis via chemical rescue, pathway placement upstream of cGMP-PKG; single lab but multiple orthogonal methods","pmids":["39808636"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"PF3D7_1414400 (PP1) regulates the mechanical properties (deformability and permeability) of mature gametocyte-infected erythrocytes through dephosphorylation of protein kinase A (PKA) substrates, which is required for gametocyte persistence in the bloodstream; PP1 also controls gametocyte activation into gametes via stimulation of the cGMP/PKG signaling pathway.","method":"Conditional depletion of PP1 in gametocytes, functional analysis of gametocyte deformability and permeability, phosphoproteomic identification of PKA substrates, cGMP/PKG pathway assay, mosquito transmission assays","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional depletion with mechanistic pathway identification (PKA substrate dephosphorylation, cGMP/PKG activation); multiple orthogonal functional readouts, single lab","pmids":["40823845"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1414400 (PP1) is a conserved serine/threonine phosphatase whose catalytic activity is essential throughout the P. falciparum life cycle: it is required for intraerythrocytic DNA synthesis/replication, is exported to the Maurer's clefts where it dephosphorylates PfSBP1 to permit merozoite release, acts upstream of the cGMP-PKG-Ca2+ signaling cascade to regulate rounding-up of the parasitophorous vacuole as the initiating step of egress (with GCα as a direct functional target), and in gametocytes dephosphorylates PKA substrates to maintain host-cell deformability and stimulates cGMP/PKG signaling for gamete activation; its activity is modulated by a growing set of regulatory partners—including PfLRR1/Sds22 (inhibitory), PfI2 (inhibitory, two-site RVxF + FxxR/KxR/K interaction), PfI3 (activating), GEXP15 (activating, via RVxF), PfRCC-PIP, PfeIF2β, and PfpTKL—that direct its substrate specificity and subcellular targeting across asexual and sexual parasite stages."},"narrative":{"mechanistic_narrative":"PF3D7_1414400 (PP1) is a conserved 304-residue serine/threonine protein phosphatase whose catalytic activity is essential throughout the P. falciparum intraerythrocytic and sexual life cycle [PMID:12057017]. Its enzymatic mechanism was established by recombinant phosphatase assays, PP1-class inhibitor sensitivity (calyculin A), and active-site mutagenesis, and heterologous complementation of the yeast glc7 mutant confirmed its catalytic conservation; knockdown of PP1 blocks parasite DNA synthesis, establishing a requirement in intraerythrocytic replication [PMID:12057017, PMID:12062492]. PP1 governs egress at multiple steps: it is exported to the Maurer's clefts where it dephosphorylates the amino-terminal domain of PfSBP1, and its inhibition blocks merozoite release [PMID:16548885]; conditional and inducible depletion further shows PP1 is essential for egress, controlling rounding-up of the parasitophorous vacuole as the initiating step by acting upstream of the cGMP-PKG-Ca2+ cascade through modulation of guanylyl cyclase alpha (GCα) activity, with calcium ionophore bypassing the PP1-null defect [PMID:32669539, PMID:39808636]. In gametocytes, PP1 dephosphorylates PKA substrates to maintain infected-erythrocyte deformability and stimulates cGMP/PKG signaling for gamete activation, functions required for transmission [PMID:40823845]; in the P. berghei ortholog PP1 is also required for mitotic exit during male gametogenesis and zygote polarity in the mosquito midgut [PMID:34145386]. Consistent with the PP1 holoenzyme paradigm, its activity and targeting are directed by a set of regulatory partners engaging conserved docking motifs (notably RVxF): the inhibitory PfLRR1/Sds22 and PfI2 (two-site RVxF plus FxxR/KxR/K binding), and the activating PfI3, GEXP15, PfRCC-PIP, PfeIF2β, and the pseudokinase PfpTKL [PMID:16629662, PMID:22128182, PMID:23837822, PMID:25132288, PMID:27303372, PMID:30429842, PMID:31148576, PMID:37628837].","teleology":[{"year":2002,"claim":"Establishing that PF3D7_1414400 is a bona fide, catalytically active PP1-class phosphatase was the prerequisite for assigning it any cellular role; enzymatic reconstitution and knockdown showed it is required for parasite DNA synthesis.","evidence":"Recombinant phosphatase assay, inhibitor profiling, active-site mutagenesis, and siRNA knockdown with a DNA synthesis readout, plus yeast glc7 complementation","pmids":["12057017","12062492"],"confidence":"High","gaps":["Direct physiological substrates for the replication role not identified","Mechanism linking PP1 activity to DNA synthesis unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Localization of PP1 to exported Maurer's clefts and identification of PfSBP1 as a dephosphorylation target tied PP1 activity to a specific export-compartment substrate and to merozoite release.","evidence":"Immunolocalization/fractionation, reciprocal co-immunoprecipitation, and calyculin A inhibition with phosphorylation and egress readouts","pmids":["16548885"],"confidence":"High","gaps":["Whether PfSBP1 dephosphorylation is directly causal for egress vs correlative not fully resolved","How PP1 is exported and retained at Maurer's clefts unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Identification of PfLRR1/Sds22 as an inhibitory PP1 partner active in cell-cycle control opened the question of how PP1 activity is regulated by binding proteins rather than being constitutive.","evidence":"GST pull-down, co-IP from parasite lysate, in vitro phosphatase assay, and Xenopus oocyte GVBD functional assay","pmids":["16629662"],"confidence":"High","gaps":["Endogenous cell-cycle substrates of the PP1–LRR1 complex in parasite not defined","Xenopus GVBD is a heterologous proxy for parasite cell cycle"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"claim":"Discovery of PfI3 as a high-affinity partner that activates rather than inhibits PP1 revealed that Plasmodium PP1 regulators diverge functionally from their yeast/human homologs.","evidence":"NMR, in vitro binding and phosphatase assays, W45A mutagenesis, GFP localization, and reverse genetics","pmids":["22128182"],"confidence":"High","gaps":["Physiological consequence of PfI3-driven activation on specific substrates unknown","Nuclear function of the PP1–I3 pairing uncharacterized"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Mapping the two-site (RVxF plus FxxR/KxR/K) architecture of the PfI2–PP1 interaction defined druggable docking surfaces and demonstrated that competing peptides have antiplasmodial activity.","evidence":"NMR, dual-motif mutagenesis, Xenopus GVBD assay, and antiplasmodial penetrating-peptide assays with infected-erythrocyte accumulation","pmids":["23837822","25132288"],"confidence":"High","gaps":["In-parasite substrates controlled by the PP1–I2 complex not enumerated","Peptide antiplasmodial mechanism assumed but not proven to act via PP1 in situ"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2016,"claim":"Identification of PfeIF2β as a two-motif PP1 partner co-localizing in cytoplasm and nucleus extended PP1 regulation to translation-associated machinery across compartments.","evidence":"In vitro interaction with motif mutagenesis, Xenopus GVBD assay, subcellular fractionation, and reverse genetics","pmids":["27303372"],"confidence":"Medium","gaps":["Functional consequence of PP1–eIF2β interaction on translation not tested","Localization by fractionation only, single lab"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"Characterization of PfRCC-PIP and the pseudokinase PfpTKL as RVxF-dependent PP1 regulators showed PP1 is embedded in scaffolds that can co-organize kinase and phosphatase activities.","evidence":"In vitro pull-down/motif mapping, co-IP from parasite, and Xenopus oocyte maturation/PP1 activity assays; reverse genetics","pmids":["30429842","31148576"],"confidence":"Medium","gaps":["Direct parasite substrates of these scaffolded complexes unknown","Regulatory direction inferred largely from heterologous oocyte assays"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Conditional knockdown with phosphoproteomics separated PP1's roles, showing it is absolutely essential for egress (vs merely required for efficient replication) and identifying GCα and a HECT E3 ligase as direct functional targets with phosphatidylcholine as an upstream lipid stimulus.","evidence":"Chemical-genetic conditional knockdown, phosphoproteomics, epistasis, and phosphatidylcholine stimulation assays","pmids":["32669539"],"confidence":"High","gaps":["Direct dephosphorylation of GCα by PP1 vs indirect regulation not fully resolved","How PC sensing is transduced to PP1 unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"Ortholog interactome mapping and genetic depletion in P. berghei confirmed the PP1–LRR1 inhibitory complex across asexual and sexual stages and placed I3 phosphorylation under its control, linking regulator hierarchy to oocyst development.","evidence":"Co-IP from parasite, phosphatase assay, PbLRR1 depletion with phosphoproteomics, and mCherry-affinity interactome MS","pmids":["35920043","35162991"],"confidence":"High","gaps":["Species-generalization of P. berghei findings to PF3D7_1414400 not directly shown for all partners","Direct substrates among interactome hits (spliceosome/proteasome) not validated"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2023,"claim":"Confirmation of the activating GEXP15–PP1 interaction in P. falciparum via the RVxF motif, with nuclear localization and ribosome association, generalized the P. berghei finding and connected PP1 to translational machinery.","evidence":"In vitro interaction with RVxF mutagenesis, phosphatase assay, live microscopy, co-IP/MS, and recombinant GYF-domain pull-down; P. berghei precedent by GEXP15","pmids":["37628837","31348803"],"confidence":"High","gaps":["Functional consequence of GEXP15-directed PP1 activity on ribosome/RNA-binding substrates not defined","Stage-specific role of the complex unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2025,"claim":"Inducible knockout resolved the initiating step of egress, showing PP1 controls parasitophorous vacuole rounding-up upstream of cGMP-PKG via GCα/cGMP homeostasis, with Ca2+ ionophore bypass placing rounding-up downstream of PP1-dependent Ca2+ signaling.","evidence":"Conditional PP1 iKO, fluorescent PV-morphology reporters, live egress imaging, and chemical rescue with egress inducers and A23187","pmids":["39808636"],"confidence":"High","gaps":["Direct dephosphorylation target on GCα controlling basal activity not pinpointed","Molecular events driving PV rounding-up downstream of Ca2+ not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Conditional gametocyte depletion extended PP1 function to transmission biology, showing it maintains infected-erythrocyte deformability via PKA-substrate dephosphorylation and drives gamete activation via cGMP/PKG.","evidence":"Conditional depletion in gametocytes, deformability/permeability assays, phosphoproteomics of PKA substrates, cGMP/PKG assays, and mosquito transmission assays","pmids":["40823845"],"confidence":"High","gaps":["Specific PKA substrates mediating mechanical properties not individually validated","How a single phosphatase coordinates opposing PKA and PKG signaling arms unclear"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How the many competing regulators (LRR1, I2, I3, GEXP15, RCC-PIP, eIF2β, pTKL) are hierarchically or temporally coordinated to direct PP1 to its stage-specific substrates in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model of regulator competition/succession across stages","Most direct parasite substrates beyond PfSBP1 and GCα remain unidentified","Structural basis of holoenzyme assembly with each regulator incomplete"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PP1–PfLRR1/Sds22 (inhibitory)","PP1–PfI2 (two-site RVxF + FxxR/KxR/K)","PP1–PfI3 (activating)","PP1–GEXP15 (activating, RVxF; ribosome-associated)","PP1–PfRCC-PIP","PP1–PfeIF2β","PP1–PfpTKL (pseudokinase scaffold)"],"partners":["PFSBP1","PFLRR1/SDS22","PFI2","PFI3","GEXP15","PFRCC-PIP","PFEIF2Β","PFPTKL","GCΑ (GUANYLYL CYCLASE ALPHA)","HECT E3 UBIQUITIN LIGASE"],"other_free_text":["Catalytic activity confirmed by inhibitor sensitivity (calyculin A) and active-site mutagenesis [#0]; functionally complements yeast glc7 [#1].","Acts upstream of the cGMP-PKG-Ca2+ cascade controlling parasitophorous vacuole rounding-up during egress; Ca2+ ionophore A23187 bypasses PP1-null defect [#11, #16].","In gametocytes dephosphorylates PKA substrates to maintain infected-erythrocyte deformability and stimulates cGMP/PKG for gamete activation [#17].","P. berghei ortholog required for mitotic exit in male gametogenesis and zygote polarity in mosquito midgut [#12].","PfI2- and PfI3-derived motif peptides that compete for PP1 docking show antiplasmodial activity [#5, #6]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"12057017","id":"PMC_12057017","title":"Characterisation and expression of a PP1 serine/threonine protein phosphatase (PfPP1) from the malaria parasite, Plasmodium falciparum: demonstration of its essential role using RNA interference.","date":"2002","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/12057017","citation_count":58,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PfPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18793411","id":"PMC_18793411","title":"The protein-phosphatome of the human malaria parasite Plasmodium falciparum.","date":"2008","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/18793411","citation_count":57,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16387795","id":"PMC_16387795","title":"Use of penetrating peptides interacting with PP1/PP2A proteins as a general approach for a drug phosphatase technology.","date":"2005","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16387795","citation_count":45,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32669539","id":"PMC_32669539","title":"Co-option of Plasmodium falciparum PP1 for egress from host erythrocytes.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32669539","citation_count":40,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PfPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16548885","id":"PMC_16548885","title":"Protein phosphatase 1, a Plasmodium falciparum essential enzyme, is exported to the host cell and implicated in the release of infectious merozoites.","date":"2006","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16548885","citation_count":40,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16629662","id":"PMC_16629662","title":"Regulation of protein phosphatase type 1 and cell cycle progression by PfLRR1, a novel leucine-rich repeat protein of the human malaria parasite Plasmodium 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22128182","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PfPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31348803","id":"PMC_31348803","title":"Essential role of GEXP15, a specific Protein Phosphatase type 1 partner, in Plasmodium berghei in asexual erythrocytic proliferation and transmission.","date":"2019","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/31348803","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25132288","id":"PMC_25132288","title":"Identification of a Plasmodium falciparum inhibitor-2 motif involved in the binding and regulation activity of protein phosphatase type 1.","date":"2014","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/25132288","citation_count":14,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PfPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27303372","id":"PMC_27303372","title":"Identification of Plasmodium falciparum Translation Initiation eIF2β Subunit: Direct Interaction with Protein Phosphatase Type 1.","date":"2016","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27303372","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PfPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33036936","id":"PMC_33036936","title":"The Multifaceted Role of Protein Phosphatase 1 in Plasmodium.","date":"2020","source":"Trends in parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/33036936","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30429842","id":"PMC_30429842","title":"Characterization of a Protein Phosphatase Type-1 and a Kinase Anchoring Protein in Plasmodium falciparum.","date":"2018","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30429842","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PfPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31148576","id":"PMC_31148576","title":"Plasmodium pseudo-Tyrosine Kinase-like binds PP1 and SERA5 and is exported to host erythrocytes.","date":"2019","source":"Scientific 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/35920043","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PbPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27159136","id":"PMC_27159136","title":"Phosphatases are emerging as novel druggable targets in Plasmodium.","date":"2016","source":"Future microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/27159136","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35162991","id":"PMC_35162991","title":"Mapping PP1c and Its Inhibitor 2 Interactomes Reveals Conserved and Specific Networks in Asexual and Sexual Stages of Plasmodium.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35162991","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37628837","id":"PMC_37628837","title":"Characterization of GEXP15 as a Potential Regulator of Protein Phosphatase 1 in Plasmodium falciparum.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37628837","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40823845","id":"PMC_40823845","title":"Plasmodium falciparum PP1 phosphatase is a key regulator of malaria parasite transmission.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/40823845","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP1","PfPP1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13931,"output_tokens":5985,"usd":0.065784,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12858,"output_tokens":5717,"usd":0.103608,"stage2_stop_reason":"end_turn"},"total_usd":0.169392,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"PF3D7_1414400 (PP1) encodes a 304-amino acid serine/threonine phosphatase with potent phosphatase activity in vitro; sensitivity to PP1-class inhibitors (e.g., calyculin A) and mutational analysis of catalytic residues confirmed its enzymatic mechanism; siRNA knockdown of PP1 inhibited parasite DNA synthesis, establishing an essential role in intraerythrocytic replication.\",\n      \"method\": \"Recombinant protein phosphatase assay, inhibitor sensitivity profiling, active-site mutagenesis, siRNA knockdown with DNA synthesis readout\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic reconstitution with mutagenesis, inhibitor profiling, and functional siRNA knockdown in parasite; multiple orthogonal methods in one study\",\n      \"pmids\": [\"12057017\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PF3D7_1414400 (PP1) functionally complements the glc7 (PP1) mutant of Saccharomyces cerevisiae, rescuing the low-glycogen phenotype, demonstrating conserved catalytic function and interaction with yeast proteins of the glycogen metabolism pathway; calyculin A (but not okadaic acid) caused hyperphosphorylation of a 51 kDa parasite protein, indicating predominant PP1 (over PP2A) activity in intraerythrocytic parasites.\",\n      \"method\": \"Yeast complementation assay (glc7 mutant rescue), phosphatase inhibitor treatment with phosphoprotein detection\",\n      \"journal\": \"International journal for parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — heterologous complementation with functional readout, supported by inhibitor pharmacology; single lab but two orthogonal methods\",\n      \"pmids\": [\"12062492\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PF3D7_1414400 (PP1) is exported to the Maurer's clefts in the host erythrocyte cytoplasm, where it modulates the phosphorylation status of the amino-terminal domain of PfSBP1 (a trans-membrane Maurer's cleft protein); co-immunoprecipitation confirmed the PP1–PfSBP1 interaction; inhibition of PP1 with calyculin A caused hyperphosphorylation of PfSBP1 and blocked merozoite release, demonstrating that PP1 activity in the Maurer's clefts is required for parasite egress.\",\n      \"method\": \"Subcellular fractionation/immunolocalization, co-immunoprecipitation, calyculin A inhibition with phosphorylation and egress readouts\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, direct localization experiment tied to functional consequence (egress block), multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"16548885\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PF3D7_1414400 (PP1) interacts with PfLRR1 (the P. falciparum Sds22 orthologue) as shown by GST pull-down and co-immunoprecipitation from parasite extracts; PfLRR1 inhibits PP1 phosphatase activity; in Xenopus oocytes PfLRR1 overcame the G2/M checkpoint to promote germinal vesicle breakdown (GVBD), mirroring effects of anti-PP1 antibodies or okadaic acid, placing PP1 regulation by PfLRR1 in cell cycle control.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation from parasite lysate, in vitro phosphatase activity assay, Xenopus oocyte GVBD functional assay\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro binding + activity assay + heterologous functional rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"16629662\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PF3D7_1414400 (PP1) binds PfI3 (a P. falciparum Inhibitor-3 homolog) with high affinity (apparent KD ~100 nM) via the conserved KVVRW motif (Trp45 critical); unlike yeast/human I3, PfI3 increases PP1 phosphatase activity in vitro; PfI3 localizes to the nucleus of all blood-stage parasites (GFP tagging) and is essential for blood-stage survival (no viable knockouts obtained).\",\n      \"method\": \"NMR (structural characterization of PfI3), in vitro binding assays (multiple methods), in vitro phosphatase activity assay, site-directed mutagenesis (W45A), GFP localization, reverse genetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR, in vitro reconstitution with mutagenesis, activity assay, and localization; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22128182\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PF3D7_1414400 (PP1) interacts with PfI2 (P. falciparum Inhibitor-2) via RVxF and HYNE motifs; both motifs are critical for binding and inhibition of PP1 phosphatase activity; PfI2 can overcome the G2/M checkpoint in Xenopus oocytes (GVBD), and peptides from PfI2 competing with RVxF binding sites in PP1 show antiplasmodial activity against blood-stage parasites in vitro.\",\n      \"method\": \"Biochemical interaction assays, in vitro phosphatase activity assay, site-directed mutagenesis of PfI2 motifs, Xenopus oocyte GVBD assay, antiplasmodial peptide assay\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with mutagenesis, functional heterologous assay, and antiplasmodial validation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23837822\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PF3D7_1414400 (PP1) engages PfI2 through a two-site interaction: the canonical RVxF motif and a second FxxR/KxR/K motif (residues D94–T117); NMR spectroscopy identified the second site; mutation of either motif alone prevented PfI2-triggered GVBD in Xenopus oocytes, while only combined mutations abolished PP1 binding, showing that tight two-site association is necessary for PP1 regulation; a penetrating peptide derived from the FxxR/KxR/K motif accumulated specifically in infected erythrocytes and displayed antiplasmodial activity.\",\n      \"method\": \"NMR spectroscopy, site-directed mutagenesis of both binding motifs, Xenopus oocyte GVBD functional assay, antiplasmodial peptide assay with infected erythrocyte accumulation\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural definition, mutagenesis of both interaction sites, functional validation in heterologous model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25132288\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PF3D7_1414400 (PP1) directly interacts with PfeIF2β (eukaryotic translation initiation factor 2β) via two binding motifs (FGEKKK and KVAW); both motifs are required for PP1 binding and for inducing GVBD in Xenopus oocytes; PP1 and PfeIF2β co-localize in cytoplasm and nuclear fractions of P. falciparum, suggesting regulation of PP1 in both compartments; attempts to knock out PfeIF2β were unsuccessful, indicating its essential role.\",\n      \"method\": \"In vitro interaction assay, site-directed mutagenesis of PfeIF2β binding motifs, Xenopus oocyte GVBD assay, subcellular fractionation, reverse genetics\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction with mutagenesis and functional Xenopus assay; localization by fractionation; single lab\",\n      \"pmids\": [\"27303372\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PF3D7_1414400 (PP1) directly interacts with PfRCC-PIP in vitro and forms a complex with it in the parasite; in Xenopus oocytes, RCC-PIP interacts with endogenous PP1 and acts in synergy with suboptimal progesterone to trigger oocyte maturation, suggesting a regulatory (activating) effect on PP1; RCC-PIP also interacts with the parasite kinase CDPK7 via its RCC1 motifs, indicating it is a dual kinase/phosphatase anchoring protein.\",\n      \"method\": \"In vitro pull-down, co-immunoprecipitation from parasite extracts, Xenopus oocyte maturation assay, reverse genetics\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding assay and functional heterologous assay; single lab, multiple methods\",\n      \"pmids\": [\"30429842\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PF3D7_1414400 (PP1) interacts with the pseudokinase PfpTKL via its SAM/RVxF motif; PP1 catalytic activity in Xenopus oocytes is modulated in an RVxF-dependent manner by pTKL, suggesting a scaffolding/regulatory role for pTKL toward PP1.\",\n      \"method\": \"In vitro interaction assay (SAM and RVxF motif mapping), Xenopus oocyte PP1 activity assay, reverse genetics in P. berghei\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding motif mapping and heterologous functional assay; single lab\",\n      \"pmids\": [\"31148576\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In P. berghei, PP1 (orthologue of PF3D7_1414400) interacts with GEXP15 via the RVxF binding motif; GEXP15 increases PP1 phosphatase activity in vitro; mutation of the RVxF motif abolishes this regulatory effect; immunoprecipitation with mass spectrometry confirmed the PP1–GEXP15 complex in both schizont and gametocyte stages, with associated proteins linked to spliceosome and proteasome pathways.\",\n      \"method\": \"In vitro interaction assay (RVxF mutagenesis), in vitro phosphatase activity assay, co-immunoprecipitation with mass spectrometry, phenotypic analysis of GEXP15-deficient P. berghei\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution with mutagenesis, activity assay, Co-IP/MS from parasite; replicated in P. falciparum context (PMID 37628837)\",\n      \"pmids\": [\"31348803\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PF3D7_1414400 (PP1) is absolutely essential for egress of P. falciparum merozoites from host erythrocytes (but only required for efficient replication); phosphoproteomic and chemical-genetic analysis identified two direct functional targets of PP1 for egress: a HECT E3 ubiquitin ligase and GCα (a fusion guanylyl cyclase/phospholipid transporter); phosphatidylcholine stimulates PP1-dependent egress, implicating PP1 in lipid sensing via GCα.\",\n      \"method\": \"Conditional knockdown (chemical-genetic), phosphoproteomics, chemical-genetic epistasis analysis, phosphatidylcholine stimulation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chemical-genetic conditional knockdown combined with phosphoproteomics and epistasis analysis; multiple orthogonal methods identifying pathway targets\",\n      \"pmids\": [\"32669539\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PP1 (P. berghei orthologue of PF3D7_1414400) is required for mitotic exit during rapid male gamete formation and potentially for establishing cell polarity during zygote development in the mosquito midgut; conditional knockdown combined with live-cell imaging, RNA-seq, and proteomics showed these roles in sexual/mosquito stages.\",\n      \"method\": \"Conditional gene knockdown, real-time live-cell imaging, ultrastructural imaging, RNA-seq, proteomics\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KD with defined cellular phenotypes (mitotic exit, cell polarity) and multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"34145386\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In P. berghei, PP1 (orthologue of PF3D7_1414400) forms a complex with PbLRR1 (Sds22 orthologue) in both asexual and sexual stages; PbLRR1 inhibits PP1 phosphatase activity; LRR1 depletion adversely affects oocyst development; phosphoproteomic analysis showed that Inhibitor-3 (I3) is drastically hypophosphorylated in LRR1-depleted parasites, suggesting that the phosphorylation status of I3 is controlled by the PP1–LRR1 complex.\",\n      \"method\": \"Co-immunoprecipitation from parasite extracts, in vitro phosphatase activity assay, genetic depletion of PbLRR1, interactome/phosphoproteomics\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro activity assay, Co-IP from native parasite, phosphoproteomics with genetic depletion; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35920043\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PF3D7_1414400 (PP1) interactome mapped by mCherry-affinity pulldown followed by mass spectrometry in P. berghei asexual and sexual stages; PP1c-associated proteins are enriched in cellular component assembly (both stages), biosynthetic processes/translation (schizonts), and protein transport (gametocytes); nuclear export mediator factor and peptidyl-prolyl cis-trans isomerase were identified as potential targets of the PP1c/I2 complex in both stages.\",\n      \"method\": \"mCherry affinity pulldown from transgenic P. berghei, mass spectrometry interactome mapping\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown/MS interactome; single lab, single method for each identified partner\",\n      \"pmids\": [\"35162991\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PF3D7_1414400 (PP1) directly interacts with GEXP15 in P. falciparum via the RVxF binding motif; this interaction enhances PP1 phosphatase activity; GEXP15 localizes predominantly to the nucleus in late asexual stages (live microscopy of tagged line); immunoprecipitation/mass spectrometry identified GEXP15 interaction with ribosomal and RNA-binding proteins, and pull-down of GEXP15 domains confirmed binding to the ribosomal complex via the GYF domain.\",\n      \"method\": \"In vitro interaction assay (RVxF mutagenesis), in vitro phosphatase activity assay, live microscopy of GFP/mCherry-tagged line, co-immunoprecipitation with mass spectrometry, recombinant domain pull-down\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with mutagenesis, activity assay, localization, and Co-IP/MS; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37628837\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PF3D7_1414400 (PP1) controls the initiation of egress by regulating rounding-up of the parasitophorous vacuole, a step that is almost completely abolished in PP1-null schizonts; PP1 acts upstream of the cGMP-PKG signaling pathway by modulating basal guanylyl cyclase alpha (GCα) activity, thus controlling cGMP homeostasis and PKG-dependent Ca2+ signaling; the calcium ionophore A23187 bypasses the PP1-null egress defect, demonstrating Ca2+-dependence of rounding-up downstream of PP1.\",\n      \"method\": \"Conditional PP1 inducible knockout (iKO), fluorescent reporters of parasitophorous vacuole morphology, live microscopy of egress kinetics, chemical rescue with egress inducers and Ca2+ ionophore\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with live-imaging morphological readout, epistasis via chemical rescue, pathway placement upstream of cGMP-PKG; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39808636\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PF3D7_1414400 (PP1) regulates the mechanical properties (deformability and permeability) of mature gametocyte-infected erythrocytes through dephosphorylation of protein kinase A (PKA) substrates, which is required for gametocyte persistence in the bloodstream; PP1 also controls gametocyte activation into gametes via stimulation of the cGMP/PKG signaling pathway.\",\n      \"method\": \"Conditional depletion of PP1 in gametocytes, functional analysis of gametocyte deformability and permeability, phosphoproteomic identification of PKA substrates, cGMP/PKG pathway assay, mosquito transmission assays\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional depletion with mechanistic pathway identification (PKA substrate dephosphorylation, cGMP/PKG activation); multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"40823845\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_1414400 (PP1) is a conserved serine/threonine phosphatase whose catalytic activity is essential throughout the P. falciparum life cycle: it is required for intraerythrocytic DNA synthesis/replication, is exported to the Maurer's clefts where it dephosphorylates PfSBP1 to permit merozoite release, acts upstream of the cGMP-PKG-Ca2+ signaling cascade to regulate rounding-up of the parasitophorous vacuole as the initiating step of egress (with GCα as a direct functional target), and in gametocytes dephosphorylates PKA substrates to maintain host-cell deformability and stimulates cGMP/PKG signaling for gamete activation; its activity is modulated by a growing set of regulatory partners—including PfLRR1/Sds22 (inhibitory), PfI2 (inhibitory, two-site RVxF + FxxR/KxR/K interaction), PfI3 (activating), GEXP15 (activating, via RVxF), PfRCC-PIP, PfeIF2β, and PfpTKL—that direct its substrate specificity and subcellular targeting across asexual and sexual parasite stages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1414400 (PP1) is a conserved 304-residue serine/threonine protein phosphatase whose catalytic activity is essential throughout the P. falciparum intraerythrocytic and sexual life cycle [#0]. Its enzymatic mechanism was established by recombinant phosphatase assays, PP1-class inhibitor sensitivity (calyculin A), and active-site mutagenesis, and heterologous complementation of the yeast glc7 mutant confirmed its catalytic conservation; knockdown of PP1 blocks parasite DNA synthesis, establishing a requirement in intraerythrocytic replication [#0, #1]. PP1 governs egress at multiple steps: it is exported to the Maurer's clefts where it dephosphorylates the amino-terminal domain of PfSBP1, and its inhibition blocks merozoite release [#2]; conditional and inducible depletion further shows PP1 is essential for egress, controlling rounding-up of the parasitophorous vacuole as the initiating step by acting upstream of the cGMP-PKG-Ca2+ cascade through modulation of guanylyl cyclase alpha (GC\\u03b1) activity, with calcium ionophore bypassing the PP1-null defect [#11, #16]. In gametocytes, PP1 dephosphorylates PKA substrates to maintain infected-erythrocyte deformability and stimulates cGMP/PKG signaling for gamete activation, functions required for transmission [#17]; in the P. berghei ortholog PP1 is also required for mitotic exit during male gametogenesis and zygote polarity in the mosquito midgut [#12]. Consistent with the PP1 holoenzyme paradigm, its activity and targeting are directed by a set of regulatory partners engaging conserved docking motifs (notably RVxF): the inhibitory PfLRR1/Sds22 and PfI2 (two-site RVxF plus FxxR/KxR/K binding), and the activating PfI3, GEXP15, PfRCC-PIP, PfeIF2\\u03b2, and the pseudokinase PfpTKL [#3, #4, #5, #6, #7, #8, #9, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that PF3D7_1414400 is a bona fide, catalytically active PP1-class phosphatase was the prerequisite for assigning it any cellular role; enzymatic reconstitution and knockdown showed it is required for parasite DNA synthesis.\",\n      \"evidence\": \"Recombinant phosphatase assay, inhibitor profiling, active-site mutagenesis, and siRNA knockdown with a DNA synthesis readout, plus yeast glc7 complementation\",\n      \"pmids\": [\"12057017\", \"12062492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physiological substrates for the replication role not identified\", \"Mechanism linking PP1 activity to DNA synthesis unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Localization of PP1 to exported Maurer's clefts and identification of PfSBP1 as a dephosphorylation target tied PP1 activity to a specific export-compartment substrate and to merozoite release.\",\n      \"evidence\": \"Immunolocalization/fractionation, reciprocal co-immunoprecipitation, and calyculin A inhibition with phosphorylation and egress readouts\",\n      \"pmids\": [\"16548885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PfSBP1 dephosphorylation is directly causal for egress vs correlative not fully resolved\", \"How PP1 is exported and retained at Maurer's clefts unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of PfLRR1/Sds22 as an inhibitory PP1 partner active in cell-cycle control opened the question of how PP1 activity is regulated by binding proteins rather than being constitutive.\",\n      \"evidence\": \"GST pull-down, co-IP from parasite lysate, in vitro phosphatase assay, and Xenopus oocyte GVBD functional assay\",\n      \"pmids\": [\"16629662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous cell-cycle substrates of the PP1\\u2013LRR1 complex in parasite not defined\", \"Xenopus GVBD is a heterologous proxy for parasite cell cycle\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery of PfI3 as a high-affinity partner that activates rather than inhibits PP1 revealed that Plasmodium PP1 regulators diverge functionally from their yeast/human homologs.\",\n      \"evidence\": \"NMR, in vitro binding and phosphatase assays, W45A mutagenesis, GFP localization, and reverse genetics\",\n      \"pmids\": [\"22128182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of PfI3-driven activation on specific substrates unknown\", \"Nuclear function of the PP1\\u2013I3 pairing uncharacterized\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapping the two-site (RVxF plus FxxR/KxR/K) architecture of the PfI2\\u2013PP1 interaction defined druggable docking surfaces and demonstrated that competing peptides have antiplasmodial activity.\",\n      \"evidence\": \"NMR, dual-motif mutagenesis, Xenopus GVBD assay, and antiplasmodial penetrating-peptide assays with infected-erythrocyte accumulation\",\n      \"pmids\": [\"23837822\", \"25132288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-parasite substrates controlled by the PP1\\u2013I2 complex not enumerated\", \"Peptide antiplasmodial mechanism assumed but not proven to act via PP1 in situ\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of PfeIF2\\u03b2 as a two-motif PP1 partner co-localizing in cytoplasm and nucleus extended PP1 regulation to translation-associated machinery across compartments.\",\n      \"evidence\": \"In vitro interaction with motif mutagenesis, Xenopus GVBD assay, subcellular fractionation, and reverse genetics\",\n      \"pmids\": [\"27303372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PP1\\u2013eIF2\\u03b2 interaction on translation not tested\", \"Localization by fractionation only, single lab\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterization of PfRCC-PIP and the pseudokinase PfpTKL as RVxF-dependent PP1 regulators showed PP1 is embedded in scaffolds that can co-organize kinase and phosphatase activities.\",\n      \"evidence\": \"In vitro pull-down/motif mapping, co-IP from parasite, and Xenopus oocyte maturation/PP1 activity assays; reverse genetics\",\n      \"pmids\": [\"30429842\", \"31148576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct parasite substrates of these scaffolded complexes unknown\", \"Regulatory direction inferred largely from heterologous oocyte assays\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional knockdown with phosphoproteomics separated PP1's roles, showing it is absolutely essential for egress (vs merely required for efficient replication) and identifying GC\\u03b1 and a HECT E3 ligase as direct functional targets with phosphatidylcholine as an upstream lipid stimulus.\",\n      \"evidence\": \"Chemical-genetic conditional knockdown, phosphoproteomics, epistasis, and phosphatidylcholine stimulation assays\",\n      \"pmids\": [\"32669539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct dephosphorylation of GC\\u03b1 by PP1 vs indirect regulation not fully resolved\", \"How PC sensing is transduced to PP1 unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Ortholog interactome mapping and genetic depletion in P. berghei confirmed the PP1\\u2013LRR1 inhibitory complex across asexual and sexual stages and placed I3 phosphorylation under its control, linking regulator hierarchy to oocyst development.\",\n      \"evidence\": \"Co-IP from parasite, phosphatase assay, PbLRR1 depletion with phosphoproteomics, and mCherry-affinity interactome MS\",\n      \"pmids\": [\"35920043\", \"35162991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Species-generalization of P. berghei findings to PF3D7_1414400 not directly shown for all partners\", \"Direct substrates among interactome hits (spliceosome/proteasome) not validated\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmation of the activating GEXP15\\u2013PP1 interaction in P. falciparum via the RVxF motif, with nuclear localization and ribosome association, generalized the P. berghei finding and connected PP1 to translational machinery.\",\n      \"evidence\": \"In vitro interaction with RVxF mutagenesis, phosphatase assay, live microscopy, co-IP/MS, and recombinant GYF-domain pull-down; P. berghei precedent by GEXP15\",\n      \"pmids\": [\"37628837\", \"31348803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of GEXP15-directed PP1 activity on ribosome/RNA-binding substrates not defined\", \"Stage-specific role of the complex unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Inducible knockout resolved the initiating step of egress, showing PP1 controls parasitophorous vacuole rounding-up upstream of cGMP-PKG via GC\\u03b1/cGMP homeostasis, with Ca2+ ionophore bypass placing rounding-up downstream of PP1-dependent Ca2+ signaling.\",\n      \"evidence\": \"Conditional PP1 iKO, fluorescent PV-morphology reporters, live egress imaging, and chemical rescue with egress inducers and A23187\",\n      \"pmids\": [\"39808636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct dephosphorylation target on GC\\u03b1 controlling basal activity not pinpointed\", \"Molecular events driving PV rounding-up downstream of Ca2+ not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional gametocyte depletion extended PP1 function to transmission biology, showing it maintains infected-erythrocyte deformability via PKA-substrate dephosphorylation and drives gamete activation via cGMP/PKG.\",\n      \"evidence\": \"Conditional depletion in gametocytes, deformability/permeability assays, phosphoproteomics of PKA substrates, cGMP/PKG assays, and mosquito transmission assays\",\n      \"pmids\": [\"40823845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific PKA substrates mediating mechanical properties not individually validated\", \"How a single phosphatase coordinates opposing PKA and PKG signaling arms unclear\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many competing regulators (LRR1, I2, I3, GEXP15, RCC-PIP, eIF2\\u03b2, pTKL) are hierarchically or temporally coordinated to direct PP1 to its stage-specific substrates in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model of regulator competition/succession across stages\", \"Most direct parasite substrates beyond PfSBP1 and GC\\u03b1 remain unidentified\", \"Structural basis of holoenzyme assembly with each regulator incomplete\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004722\", \"supporting_discovery_ids\": [0, 1, 3, 4, 5]},\n      {\"term_id\": \"GO:0004721\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0019888\", \"supporting_discovery_ids\": [3, 4, 5, 6, 8, 9, 10, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020036\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 7, 15]},\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071704\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0006260\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0051701\", \"supporting_discovery_ids\": [2, 11, 16]},\n      {\"term_id\": \"GO:0007165\", \"supporting_discovery_ids\": [11, 16, 17]},\n      {\"term_id\": \"GO:0019953\", \"supporting_discovery_ids\": [12, 17]}\n    ],\n    \"complexes\": [\n      \"PP1\\u2013PfLRR1/Sds22 (inhibitory)\",\n      \"PP1\\u2013PfI2 (two-site RVxF + FxxR/KxR/K)\",\n      \"PP1\\u2013PfI3 (activating)\",\n      \"PP1\\u2013GEXP15 (activating, RVxF; ribosome-associated)\",\n      \"PP1\\u2013PfRCC-PIP\",\n      \"PP1\\u2013PfeIF2\\u03b2\",\n      \"PP1\\u2013PfpTKL (pseudokinase scaffold)\"\n    ],\n    \"partners\": [\n      \"PfSBP1\",\n      \"PfLRR1/Sds22\",\n      \"PfI2\",\n      \"PfI3\",\n      \"GEXP15\",\n      \"PfRCC-PIP\",\n      \"PfeIF2\\u03b2\",\n      \"PfpTKL\",\n      \"GC\\u03b1 (guanylyl cyclase alpha)\",\n      \"HECT E3 ubiquitin ligase\"\n    ],\n    \"other_free_text\": [\n      \"Catalytic activity confirmed by inhibitor sensitivity (calyculin A) and active-site mutagenesis [#0]; functionally complements yeast glc7 [#1].\",\n      \"Acts upstream of the cGMP-PKG-Ca2+ cascade controlling parasitophorous vacuole rounding-up during egress; Ca2+ ionophore A23187 bypasses PP1-null defect [#11, #16].\",\n      \"In gametocytes dephosphorylates PKA substrates to maintain infected-erythrocyte deformability and stimulates cGMP/PKG for gamete activation [#17].\",\n      \"P. berghei ortholog required for mitotic exit in male gametogenesis and zygote polarity in mosquito midgut [#12].\",\n      \"PfI2- and PfI3-derived motif peptides that compete for PP1 docking show antiplasmodial activity [#5, #6].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1414400","name":null,"product":"serine/threonine protein phosphatase PP1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1028300","name":null,"product":"serine/threonine protein phosphatase PP1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1343700","name":null,"product":"serine/threonine protein phosphatase PP1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PP1","evaluation":null}