{"gene":"PF3D7_1423300","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2004,"finding":"P. falciparum PP7 is a Ca2+-regulated phosphatase whose EF-hand domains are essential for stimulation of phosphatase activity by Ca2+. Post-translational proteolytic processing generates a constitutively active catalytic core from the full-length PP7; the full-length enzyme is activated by Ca2+, whereas the processed core is constitutively active and either less responsive or unresponsive to Ca2+. This processing is rapid, specific, and occurs in vivo.","method":"Biochemical characterization of full-length and proteolytically processed forms in P. falciparum; in vivo processing assays; Ca2+-dependent phosphatase activity assays","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical activity assays with in vivo validation, single lab, two orthogonal approaches (activity assay + in vivo processing)","pmids":["15230980"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"PP7 (PF3D7_1423300) was identified as one of 27 protein phosphatase sequences in the P. falciparum genome, classified within the PPP family (PPEF/PP7 subfamily), representing the smallest phosphatome of any organism studied. No mechanistic detail beyond classification was established.","method":"Bioinformatics/phylogenetic analysis of the P. falciparum genome (PlasmoDB)","journal":"BMC genomics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/bioinformatic classification only, no direct experimental mechanistic data on PP7","pmids":["18793411"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"PP7 is a calcium-dependent phosphatase that is a high-confidence substrate of cAMP-dependent protein kinase (PKA). Conditional disruption of PP7 causes severe growth arrest; PP7 is dispensable for erythrocyte invasion but is essential for early ring-stage development, with PP7-null parasites arresting shortly after invasion and failing to transition to ameboid forms. PP7 physically interacts with calmodulin and calcium-dependent protein kinase 1 (CDPK1), placing it within a calcium-signaling pathway. Phosphoproteomic analysis showed that loss of PP7 alters phosphorylation of certain PKAc substrates, suggesting PP7 regulates PKAc substrate phosphorylation.","method":"Conditional genetic disruption (knock-out); co-immunoprecipitation (interaction with calmodulin and CDPK1); phosphoproteomic analysis (mass spectrometry); in vitro calcium-dependent phosphatase activity assay; phenotypic imaging of ring-stage development","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined cellular phenotype, reciprocal protein interaction (Co-IP with calmodulin and CDPK1), phosphoproteomic substrate analysis, and Ca2+-dependent activity assay all in a single rigorous study","pmids":["39387582"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"P. falciparum PP7 (PF3D7_1423300) is a calcium-dependent serine/threonine protein phosphatase that is phosphorylated by PKA, interacts with calmodulin and CDPK1 as part of a calcium-signaling module, and is essential for early ring-stage development following erythrocyte invasion (but not for invasion itself); its full-length form requires Ca2+/EF-hand domains for activation, while post-translational proteolytic processing generates a constitutively active catalytic core, and phosphoproteomic evidence indicates PP7 modulates the phosphorylation state of PKAc substrates."},"narrative":{"mechanistic_narrative":"PP7 (PF3D7_1423300) is a calcium-regulated serine/threonine protein phosphatase of Plasmodium falciparum that functions within a calcium-signaling module governing early intra-erythrocytic development [PMID:15230980, PMID:39387582]. The full-length enzyme is activated by Ca2+ through its EF-hand domains, and rapid, specific in vivo proteolytic processing generates a constitutively active catalytic core that is largely Ca2+-independent [PMID:15230980]. PP7 physically associates with calmodulin and calcium-dependent protein kinase 1 (CDPK1), and is itself a high-confidence substrate of cAMP-dependent protein kinase (PKA), linking calcium and cAMP signaling; loss of PP7 alters phosphorylation of PKAc substrates, indicating a role in shaping the phosphoproteome [PMID:39387582]. Conditional disruption shows PP7 is dispensable for erythrocyte invasion but essential immediately afterward, with PP7-null parasites arresting shortly after invasion and failing to transition to ameboid ring-stage forms [PMID:39387582]. Beyond this calcium-signaling and ring-stage developmental role, no further substrate-level mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Establishing how PP7 activity is controlled, this work showed the enzyme is a Ca2+-regulated phosphatase whose EF-hand domains are required for calcium stimulation and whose activity can be switched to a constitutive state by proteolysis.","evidence":"Biochemical activity assays on full-length and proteolytically processed forms plus in vivo processing assays in P. falciparum","pmids":["15230980"],"confidence":"Medium","gaps":["identity of the processing protease not determined","physiological trigger and timing of processing in the parasite life cycle unknown","in vivo substrates of the active enzyme not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"claim":"Genome-wide phosphatome cataloguing placed PP7 within the PPP family (PPEF/PP7 subfamily), fixing its identity as one of a small set of parasite phosphatases but adding no mechanistic function.","evidence":"Bioinformatic/phylogenetic analysis of the P. falciparum genome via PlasmoDB","pmids":["18793411"],"confidence":"Low","gaps":["computational classification only, no experimental data on PP7","no functional or cellular role assigned","no interacting partners identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"Integrating genetics, interactomics, and phosphoproteomics defined PP7's cellular role and signaling context: it is essential for early ring-stage development, sits in a calcium-signaling module with calmodulin and CDPK1, and is a PKA substrate that regulates PKAc substrate phosphorylation.","evidence":"Conditional knockout with phenotypic imaging, Co-IP with calmodulin and CDPK1, mass-spectrometry phosphoproteomics, and Ca2+-dependent activity assay in P. falciparum","pmids":["39387582"],"confidence":"High","gaps":["direct dephosphorylation substrates of PP7 not defined (altered phosphosites may be indirect)","mechanism coupling PKA phosphorylation of PP7 to its phosphatase activity unresolved","molecular basis of the post-invasion arrest and ameboid transition failure not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The direct substrate repertoire of PP7 and how its Ca2+/EF-hand regulation, proteolytic processing, and PKA phosphorylation are integrated to control ring-stage development remain unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["no validated direct substrate of PP7","no structural model of the full-length versus processed enzyme","interplay between processing, Ca2+ activation, and PKA phosphorylation uncharacterized"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["CALMODULIN (CO-IP INTERACTOR) [#2]","CDPK1 / CALCIUM-DEPENDENT PROTEIN KINASE 1 (CO-IP INTERACTOR) [#2]","PKA / CAMP-DEPENDENT PROTEIN KINASE (PHOSPHORYLATES PP7) [#2]"],"other_free_text":["Full-length PP7 is activated by Ca2+ via its EF-hand domains; rapid, specific in vivo proteolytic processing yields a constitutively active, Ca2+-insensitive catalytic core [#0].","Conditional disruption is dispensable for erythrocyte invasion but essential for early ring-stage development; PP7-null parasites arrest shortly after invasion and fail to transition to ameboid forms [#2].","Loss of PP7 alters phosphorylation of certain PKAc substrates, indicating PP7 modulates the PKAc-regulated phosphoproteome [#2].","Classified within the PPP family (PPEF/PP7 subfamily) in the P. falciparum phosphatome [#1]."]}},"prefetch_data":{},"corpus_meta":[{"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":"15230980","id":"PMC_15230980","title":"Post-translational generation of constitutively active cores from larger phosphatases in the malaria parasite, Plasmodium falciparum: implications for proteomics.","date":"2004","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15230980","citation_count":24,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"21960277","id":"PMC_21960277","title":"Prediction of biological functions of Shewanella-like protein phosphatases (Shelphs) across different domains of life.","date":"2011","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21960277","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39387582","id":"PMC_39387582","title":"Plasmodium falciparum protein phosphatase PP7 is required for early ring-stage development.","date":"2024","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/39387582","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PP7"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4941,"output_tokens":1099,"usd":0.015654,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5942,"output_tokens":2158,"usd":0.04183,"stage2_stop_reason":"end_turn"},"total_usd":0.057484,"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\": 2004,\n      \"finding\": \"P. falciparum PP7 is a Ca2+-regulated phosphatase whose EF-hand domains are essential for stimulation of phosphatase activity by Ca2+. Post-translational proteolytic processing generates a constitutively active catalytic core from the full-length PP7; the full-length enzyme is activated by Ca2+, whereas the processed core is constitutively active and either less responsive or unresponsive to Ca2+. This processing is rapid, specific, and occurs in vivo.\",\n      \"method\": \"Biochemical characterization of full-length and proteolytically processed forms in P. falciparum; in vivo processing assays; Ca2+-dependent phosphatase activity assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical activity assays with in vivo validation, single lab, two orthogonal approaches (activity assay + in vivo processing)\",\n      \"pmids\": [\"15230980\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PP7 (PF3D7_1423300) was identified as one of 27 protein phosphatase sequences in the P. falciparum genome, classified within the PPP family (PPEF/PP7 subfamily), representing the smallest phosphatome of any organism studied. No mechanistic detail beyond classification was established.\",\n      \"method\": \"Bioinformatics/phylogenetic analysis of the P. falciparum genome (PlasmoDB)\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/bioinformatic classification only, no direct experimental mechanistic data on PP7\",\n      \"pmids\": [\"18793411\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PP7 is a calcium-dependent phosphatase that is a high-confidence substrate of cAMP-dependent protein kinase (PKA). Conditional disruption of PP7 causes severe growth arrest; PP7 is dispensable for erythrocyte invasion but is essential for early ring-stage development, with PP7-null parasites arresting shortly after invasion and failing to transition to ameboid forms. PP7 physically interacts with calmodulin and calcium-dependent protein kinase 1 (CDPK1), placing it within a calcium-signaling pathway. Phosphoproteomic analysis showed that loss of PP7 alters phosphorylation of certain PKAc substrates, suggesting PP7 regulates PKAc substrate phosphorylation.\",\n      \"method\": \"Conditional genetic disruption (knock-out); co-immunoprecipitation (interaction with calmodulin and CDPK1); phosphoproteomic analysis (mass spectrometry); in vitro calcium-dependent phosphatase activity assay; phenotypic imaging of ring-stage development\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined cellular phenotype, reciprocal protein interaction (Co-IP with calmodulin and CDPK1), phosphoproteomic substrate analysis, and Ca2+-dependent activity assay all in a single rigorous study\",\n      \"pmids\": [\"39387582\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"P. falciparum PP7 (PF3D7_1423300) is a calcium-dependent serine/threonine protein phosphatase that is phosphorylated by PKA, interacts with calmodulin and CDPK1 as part of a calcium-signaling module, and is essential for early ring-stage development following erythrocyte invasion (but not for invasion itself); its full-length form requires Ca2+/EF-hand domains for activation, while post-translational proteolytic processing generates a constitutively active catalytic core, and phosphoproteomic evidence indicates PP7 modulates the phosphorylation state of PKAc substrates.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PP7 (PF3D7_1423300) is a calcium-regulated serine/threonine protein phosphatase of Plasmodium falciparum that functions within a calcium-signaling module governing early intra-erythrocytic development [#0, #2]. The full-length enzyme is activated by Ca2+ through its EF-hand domains, and rapid, specific in vivo proteolytic processing generates a constitutively active catalytic core that is largely Ca2+-independent [#0]. PP7 physically associates with calmodulin and calcium-dependent protein kinase 1 (CDPK1), and is itself a high-confidence substrate of cAMP-dependent protein kinase (PKA), linking calcium and cAMP signaling; loss of PP7 alters phosphorylation of PKAc substrates, indicating a role in shaping the phosphoproteome [#2]. Conditional disruption shows PP7 is dispensable for erythrocyte invasion but essential immediately afterward, with PP7-null parasites arresting shortly after invasion and failing to transition to ameboid ring-stage forms [#2]. Beyond this calcium-signaling and ring-stage developmental role, no further substrate-level mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing how PP7 activity is controlled, this work showed the enzyme is a Ca2+-regulated phosphatase whose EF-hand domains are required for calcium stimulation and whose activity can be switched to a constitutive state by proteolysis.\",\n      \"evidence\": \"Biochemical activity assays on full-length and proteolytically processed forms plus in vivo processing assays in P. falciparum\",\n      \"pmids\": [\"15230980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"identity of the processing protease not determined\",\n        \"physiological trigger and timing of processing in the parasite life cycle unknown\",\n        \"in vivo substrates of the active enzyme not identified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genome-wide phosphatome cataloguing placed PP7 within the PPP family (PPEF/PP7 subfamily), fixing its identity as one of a small set of parasite phosphatases but adding no mechanistic function.\",\n      \"evidence\": \"Bioinformatic/phylogenetic analysis of the P. falciparum genome via PlasmoDB\",\n      \"pmids\": [\"18793411\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"computational classification only, no experimental data on PP7\",\n        \"no functional or cellular role assigned\",\n        \"no interacting partners identified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrating genetics, interactomics, and phosphoproteomics defined PP7's cellular role and signaling context: it is essential for early ring-stage development, sits in a calcium-signaling module with calmodulin and CDPK1, and is a PKA substrate that regulates PKAc substrate phosphorylation.\",\n      \"evidence\": \"Conditional knockout with phenotypic imaging, Co-IP with calmodulin and CDPK1, mass-spectrometry phosphoproteomics, and Ca2+-dependent activity assay in P. falciparum\",\n      \"pmids\": [\"39387582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"direct dephosphorylation substrates of PP7 not defined (altered phosphosites may be indirect)\",\n        \"mechanism coupling PKA phosphorylation of PP7 to its phosphatase activity unresolved\",\n        \"molecular basis of the post-invasion arrest and ameboid transition failure not established\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct substrate repertoire of PP7 and how its Ca2+/EF-hand regulation, proteolytic processing, and PKA phosphorylation are integrated to control ring-stage development remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"no validated direct substrate of PP7\",\n        \"no structural model of the full-length versus processed enzyme\",\n        \"interplay between processing, Ca2+ activation, and PKA phosphorylation uncharacterized\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004722\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0019722\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Calmodulin (Co-IP interactor) [#2]\",\n      \"CDPK1 / calcium-dependent protein kinase 1 (Co-IP interactor) [#2]\",\n      \"PKA / cAMP-dependent protein kinase (phosphorylates PP7) [#2]\"\n    ],\n    \"other_free_text\": [\n      \"Full-length PP7 is activated by Ca2+ via its EF-hand domains; rapid, specific in vivo proteolytic processing yields a constitutively active, Ca2+-insensitive catalytic core [#0].\",\n      \"Conditional disruption is dispensable for erythrocyte invasion but essential for early ring-stage development; PP7-null parasites arrest shortly after invasion and fail to transition to ameboid forms [#2].\",\n      \"Loss of PP7 alters phosphorylation of certain PKAc substrates, indicating PP7 modulates the PKAc-regulated phosphoproteome [#2].\",\n      \"Classified within the PPP family (PPEF/PP7 subfamily) in the P. falciparum phosphatome [#1].\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1423300","name":null,"product":"serine/threonine protein phosphatase 7","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1020100","name":null,"product":"serine/threonine protein phosphatase 7","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1334700","name":null,"product":"serine/threonine protein phosphatase 7, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PP7","evaluation":null}