{"gene":"PF3D7_1319700","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":1999,"finding":"A PP2A-like enzyme was purified from cytosolic extracts of P. falciparum erythrocytic stages; it preferentially dephosphorylated the alpha subunit of phosphorylase kinase, required Mn2+ for activity, was resistant to inhibitor-1, and was inhibited by nanomolar concentrations of okadaic acid. The cDNA of this catalytic subunit was identified by matching its predicted amino acid sequence to the N-terminal sequence of the purified enzyme.","method":"Biochemical purification of phosphatase activity from cytosolic extracts, substrate specificity assays, inhibitor profiling (okadaic acid, inhibitor-1), cDNA cloning and N-terminal sequencing","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical purification with multiple functional assays (substrate specificity, inhibitor sensitivity, Mn2+ requirement) in a single study; replicated across multiple assay types but from one lab","pmids":["10340482"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"finding":"The P. falciparum aspartate-rich protein PfARP (a SET/TAF-family member) specifically inhibits parasitic PP2A (PF3D7_1319700) at nanomolar concentrations, with no inhibitory effect on PP1, PP2B, PP5, or PPJ, identifying PfARP as a candidate physiological regulator of PfPP2A.","method":"Purification of native PfARP, in vitro phosphatase inhibition assays against PP2A and related phosphatases (PP1, PP2B, PP5, PPJ), recombinant expression in bacteria","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro enzymatic inhibition assays with purified proteins, specificity confirmed across multiple phosphatases; single lab","pmids":["12615323"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"PfPTPA (PhosphoTyrosyl Phosphatase Activator) physically binds to and activates PfPP2A (PF3D7_1319700) in vitro; both proteins co-localize in the same compartment of blood stage parasites. Mutation of three PfPTPA residues (V283, G292, M296) abolishes the interaction, and G292 is essential for its activating activity.","method":"In vitro binding assays, PP2A activity assays, site-directed mutagenesis of PfPTPA, subcellular co-localization studies in blood stage parasites, Xenopus oocyte functional assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding and functional assays combined with mutagenesis establishing the molecular basis of PfPTPA–PfPP2A interaction; single lab with multiple orthogonal methods","pmids":["24521882"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1319700 (PfPP2A) encodes a Mn2+-dependent, okadaic acid-sensitive Ser/Thr phosphatase that dephosphorylates phosphoserine/phosphothreonine substrates in the P. falciparum cytosol; its activity is specifically inhibited at nanomolar concentrations by the parasite's own SET/TAF-family protein PfARP, and is activated by PfPTPA, which binds PfPP2A through residues V283, G292, and M296 to stimulate its phosphatase activity, implicating PfPP2A in cell cycle regulation during intraerythrocytic development."},"narrative":{"mechanistic_narrative":"PF3D7_1319700 encodes a PP2A-like Ser/Thr protein phosphatase active in the cytosol of P. falciparum erythrocytic stages, where it dephosphorylates phosphoserine/phosphothreonine substrates including the alpha subunit of phosphorylase kinase; the enzyme requires Mn2+, is resistant to inhibitor-1, and is inhibited by nanomolar okadaic acid, the biochemical signature by which its catalytic activity was first defined [PMID:10340482]. Its activity is tuned by two dedicated parasite regulators: the SET/TAF-family aspartate-rich protein PfARP specifically inhibits PF3D7_1319700 at nanomolar concentrations without affecting PP1, PP2B, PP5, or PPJ [PMID:12615323], while PfPTPA physically binds and activates the phosphatase, an interaction dependent on PfPTPA residues V283, G292, and M296 and with G292 essential for activation [PMID:24521882]. PfPTPA and PF3D7_1319700 co-localize in the same compartment of blood-stage parasites [PMID:24521882]. Note that the timeline characterizes PF3D7_1319700 primarily through the enzymology of its purified activity and the identity of its regulators; the discrete substrate repertoire, physiological targets, and in vivo role of this phosphatase have not been characterized in the available corpus.","teleology":[{"year":1999,"claim":"Whether P. falciparum possesses a distinct PP2A-type phosphatase was unknown; biochemical purification defined a Mn2+-dependent, okadaic acid-sensitive cytosolic enzyme and linked it to the PF3D7_1319700 catalytic subunit, establishing the enzyme's existence and core catalytic properties.","evidence":"biochemical purification of phosphatase activity from erythrocytic-stage cytosolic extracts, substrate specificity and inhibitor profiling, cDNA cloning matched to N-terminal sequence of the purified enzyme","pmids":["10340482"],"confidence":"Medium","gaps":["physiological substrates beyond phosphorylase kinase alpha subunit not identified","subcellular and stage-specific localization not resolved","no genetic or in vivo functional test of the enzyme"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2003,"claim":"How the phosphatase is negatively regulated was unaddressed; the SET/TAF-family protein PfARP was shown to inhibit PF3D7_1319700 at nanomolar concentrations without acting on other parasite phosphatases, identifying a specific candidate physiological inhibitor.","evidence":"in vitro phosphatase inhibition assays with purified native and recombinant PfARP against PP2A, PP1, PP2B, PP5, and PPJ","pmids":["12615323"],"confidence":"Medium","gaps":["physical binding site of PfARP on PF3D7_1319700 not mapped","in vivo relevance of the inhibition not demonstrated","conditions triggering PfARP-mediated inhibition unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"The positive regulatory input to the phosphatase was undefined; PfPTPA was shown to bind and activate PF3D7_1319700 and to co-localize with it in blood stages, with mutagenesis pinpointing V283, G292, and M296 as the interaction determinants and G292 as essential for activation, establishing the molecular basis of an activating partner.","evidence":"in vitro binding and PP2A activity assays, site-directed mutagenesis of PfPTPA, subcellular co-localization in blood-stage parasites, Xenopus oocyte functional assays","pmids":["24521882"],"confidence":"Medium","gaps":["interaction interface on PF3D7_1319700 itself not defined","downstream substrates activated by the PfPTPA-PfPP2A complex not identified","no genetic disruption to confirm the pathway in vivo"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The endogenous substrate repertoire, in vivo role in intraerythrocytic development, and structural basis of regulator binding for PF3D7_1319700 remain to be determined.","evidence":"no discovery in the corpus addresses substrates, genetic essentiality, or structure of the phosphatase in vivo","pmids":[],"confidence":"Medium","gaps":["no physiological substrate map","no genetic knockout/knockdown phenotype","no structural model of PF3D7_1319700 or its regulator complexes"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFARP (SET/TAF-FAMILY ASPARTATE-RICH PROTEIN; NANOMOLAR INHIBITOR OF PF3D7_1319700)","PFPTPA (PHOSPHOTYROSYL PHOSPHATASE ACTIVATOR; BINDS AND ACTIVATES PF3D7_1319700)"],"other_free_text":["Catalytic activity requires Mn2+, is resistant to inhibitor-1, and is inhibited by nanomolar okadaic acid [#0]","PfPTPA interaction depends on PfPTPA residues V283, G292, and M296, with G292 essential for activation [#2]","Characterized in Plasmodium falciparum erythrocytic (blood) stages"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"10340482","id":"PMC_10340482","title":"Characterization of protein Ser/Thr phosphatases of the malaria parasite, Plasmodium falciparum: inhibition of the parasitic calcineurin by cyclophilin-cyclosporin complex.","date":"1999","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/10340482","citation_count":53,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP2A"],"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":["PP2A"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12615323","id":"PMC_12615323","title":"Characterization of a unique aspartate-rich protein of the SET/TAF-family in the human malaria parasite, Plasmodium falciparum, which inhibits protein phosphatase 2A.","date":"2003","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/12615323","citation_count":21,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP2A"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24521882","id":"PMC_24521882","title":"PhosphoTyrosyl phosphatase activator of Plasmodium falciparum: identification of its residues involved in binding to and activation of PP2A.","date":"2014","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24521882","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP2A","PfPP2A"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5000,"output_tokens":1119,"usd":0.015893,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5918,"output_tokens":2278,"usd":0.04327,"stage2_stop_reason":"end_turn"},"total_usd":0.059163,"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\": 1999,\n      \"finding\": \"A PP2A-like enzyme was purified from cytosolic extracts of P. falciparum erythrocytic stages; it preferentially dephosphorylated the alpha subunit of phosphorylase kinase, required Mn2+ for activity, was resistant to inhibitor-1, and was inhibited by nanomolar concentrations of okadaic acid. The cDNA of this catalytic subunit was identified by matching its predicted amino acid sequence to the N-terminal sequence of the purified enzyme.\",\n      \"method\": \"Biochemical purification of phosphatase activity from cytosolic extracts, substrate specificity assays, inhibitor profiling (okadaic acid, inhibitor-1), cDNA cloning and N-terminal sequencing\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical purification with multiple functional assays (substrate specificity, inhibitor sensitivity, Mn2+ requirement) in a single study; replicated across multiple assay types but from one lab\",\n      \"pmids\": [\"10340482\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The P. falciparum aspartate-rich protein PfARP (a SET/TAF-family member) specifically inhibits parasitic PP2A (PF3D7_1319700) at nanomolar concentrations, with no inhibitory effect on PP1, PP2B, PP5, or PPJ, identifying PfARP as a candidate physiological regulator of PfPP2A.\",\n      \"method\": \"Purification of native PfARP, in vitro phosphatase inhibition assays against PP2A and related phosphatases (PP1, PP2B, PP5, PPJ), recombinant expression in bacteria\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro enzymatic inhibition assays with purified proteins, specificity confirmed across multiple phosphatases; single lab\",\n      \"pmids\": [\"12615323\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PfPTPA (PhosphoTyrosyl Phosphatase Activator) physically binds to and activates PfPP2A (PF3D7_1319700) in vitro; both proteins co-localize in the same compartment of blood stage parasites. Mutation of three PfPTPA residues (V283, G292, M296) abolishes the interaction, and G292 is essential for its activating activity.\",\n      \"method\": \"In vitro binding assays, PP2A activity assays, site-directed mutagenesis of PfPTPA, subcellular co-localization studies in blood stage parasites, Xenopus oocyte functional assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding and functional assays combined with mutagenesis establishing the molecular basis of PfPTPA–PfPP2A interaction; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24521882\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1319700 (PfPP2A) encodes a Mn2+-dependent, okadaic acid-sensitive Ser/Thr phosphatase that dephosphorylates phosphoserine/phosphothreonine substrates in the P. falciparum cytosol; its activity is specifically inhibited at nanomolar concentrations by the parasite's own SET/TAF-family protein PfARP, and is activated by PfPTPA, which binds PfPP2A through residues V283, G292, and M296 to stimulate its phosphatase activity, implicating PfPP2A in cell cycle regulation during intraerythrocytic development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1319700 encodes a PP2A-like Ser/Thr protein phosphatase active in the cytosol of P. falciparum erythrocytic stages, where it dephosphorylates phosphoserine/phosphothreonine substrates including the alpha subunit of phosphorylase kinase; the enzyme requires Mn2+, is resistant to inhibitor-1, and is inhibited by nanomolar okadaic acid, the biochemical signature by which its catalytic activity was first defined [#0]. Its activity is tuned by two dedicated parasite regulators: the SET/TAF-family aspartate-rich protein PfARP specifically inhibits PF3D7_1319700 at nanomolar concentrations without affecting PP1, PP2B, PP5, or PPJ [#1], while PfPTPA physically binds and activates the phosphatase, an interaction dependent on PfPTPA residues V283, G292, and M296 and with G292 essential for activation [#2]. PfPTPA and PF3D7_1319700 co-localize in the same compartment of blood-stage parasites [#2]. Note that the timeline characterizes PF3D7_1319700 primarily through the enzymology of its purified activity and the identity of its regulators; the discrete substrate repertoire, physiological targets, and in vivo role of this phosphatase have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Whether P. falciparum possesses a distinct PP2A-type phosphatase was unknown; biochemical purification defined a Mn2+-dependent, okadaic acid-sensitive cytosolic enzyme and linked it to the PF3D7_1319700 catalytic subunit, establishing the enzyme's existence and core catalytic properties.\",\n      \"evidence\": \"biochemical purification of phosphatase activity from erythrocytic-stage cytosolic extracts, substrate specificity and inhibitor profiling, cDNA cloning matched to N-terminal sequence of the purified enzyme\",\n      \"pmids\": [\"10340482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"physiological substrates beyond phosphorylase kinase alpha subunit not identified\",\n        \"subcellular and stage-specific localization not resolved\",\n        \"no genetic or in vivo functional test of the enzyme\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"How the phosphatase is negatively regulated was unaddressed; the SET/TAF-family protein PfARP was shown to inhibit PF3D7_1319700 at nanomolar concentrations without acting on other parasite phosphatases, identifying a specific candidate physiological inhibitor.\",\n      \"evidence\": \"in vitro phosphatase inhibition assays with purified native and recombinant PfARP against PP2A, PP1, PP2B, PP5, and PPJ\",\n      \"pmids\": [\"12615323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"physical binding site of PfARP on PF3D7_1319700 not mapped\",\n        \"in vivo relevance of the inhibition not demonstrated\",\n        \"conditions triggering PfARP-mediated inhibition unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The positive regulatory input to the phosphatase was undefined; PfPTPA was shown to bind and activate PF3D7_1319700 and to co-localize with it in blood stages, with mutagenesis pinpointing V283, G292, and M296 as the interaction determinants and G292 as essential for activation, establishing the molecular basis of an activating partner.\",\n      \"evidence\": \"in vitro binding and PP2A activity assays, site-directed mutagenesis of PfPTPA, subcellular co-localization in blood-stage parasites, Xenopus oocyte functional assays\",\n      \"pmids\": [\"24521882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"interaction interface on PF3D7_1319700 itself not defined\",\n        \"downstream substrates activated by the PfPTPA-PfPP2A complex not identified\",\n        \"no genetic disruption to confirm the pathway in vivo\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous substrate repertoire, in vivo role in intraerythrocytic development, and structural basis of regulator binding for PF3D7_1319700 remain to be determined.\",\n      \"evidence\": \"no discovery in the corpus addresses substrates, genetic essentiality, or structure of the phosphatase in vivo\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"no physiological substrate map\",\n        \"no genetic knockout/knockdown phenotype\",\n        \"no structural model of PF3D7_1319700 or its regulator complexes\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004722\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0030145\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0019888\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006470\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfARP (SET/TAF-family aspartate-rich protein; nanomolar inhibitor of PF3D7_1319700)\",\n      \"PfPTPA (PhosphoTyrosyl Phosphatase Activator; binds and activates PF3D7_1319700)\"\n    ],\n    \"other_free_text\": [\n      \"Catalytic activity requires Mn2+, is resistant to inhibitor-1, and is inhibited by nanomolar okadaic acid [#0]\",\n      \"PfPTPA interaction depends on PfPTPA residues V283, G292, and M296, with G292 essential for activation [#2]\",\n      \"Characterized in Plasmodium falciparum erythrocytic (blood) stages\"\n    ]\n  }\n}","audit_flag":{"gene":"PF3D7_1319700","tier":"IDENTITY_CHECK","verdict":"identity unverified","subtype":"names_other_cards","uniprot_band":"","rules_fired":"R12","issue":"No cited paper names this card; 2 of 3 cited papers name other catalogue genes (PF3D7_0909300, PF3D7_0919000, PF3D7_1355500). The summary may describe one of those genes."},"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1319700","name":null,"product":"protein phosphatase PP2A regulatory subunit A, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1418200","name":null,"product":"protein phosphatase PP2A regulatory subunit A, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1420500","name":null,"product":"protein phosphatase PP2A regulatory subunit A, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}