{"gene":"PF3D7_1246900","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2004,"finding":"PKB (PF3D7_1246900) was identified as a protein kinase B homologue in P. falciparum expressed mainly in schizonts and merozoites; it lacks a pleckstrin homology domain found in mammalian PKB. Biochemical studies demonstrated that its catalytic activation depends on autophosphorylation of a serine residue (Ser-271) in the activation loop, and that its unusual N-terminal region negatively regulates its catalytic activity.","method":"In vitro biochemical assays, autophosphorylation assays, N-terminal domain functional dissection, small-molecule inhibitor studies","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro enzymatic characterization and mutagenesis-level inference from a single lab with no independent replication reported","pmids":["15024016"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Calmodulin (CaM) was identified as the upstream activator of PKB (PF3D7_1246900). A CaM-binding domain was mapped to the N-terminal region of PKB. CaM interacts with this domain in a calcium-dependent manner and activates PKB. CaM associates with PKB in intact parasites. Phospholipase C acts as an upstream regulator of this cascade by facilitating calcium release from intracellular stores, establishing a multicomponent PLC–Ca2+–CaM–PKB signaling pathway in P. falciparum.","method":"CaM-binding domain mapping, co-immunoprecipitation (CaM with PKB in parasite lysates), calcium-dependent binding/activation assays, phospholipase C inhibitor experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP showing CaM–PKB association in parasite, calcium-dependence assays, and pathway dissection with upstream inhibitor, all from a single lab","pmids":["16809343"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PKB (PF3D7_1246900) is a P. falciparum serine/threonine kinase that lacks a pleckstrin homology domain, is expressed predominantly in schizonts and merozoites, undergoes autophosphorylation at Ser-271 in its activation loop for catalytic activation, is negatively regulated by its own N-terminal region, and is activated by calmodulin in a calcium-dependent manner downstream of phospholipase C-mediated calcium release from intracellular stores."},"narrative":{"mechanistic_narrative":"PKB (PF3D7_1246900) is a Plasmodium falciparum protein kinase B homologue that functions as a calcium-responsive serine/threonine kinase expressed predominantly in schizonts and merozoites [PMID:15024016]. Unlike mammalian PKB, it lacks a pleckstrin homology domain; instead, its unusual N-terminal region serves a negative regulatory role, and its catalytic activation requires autophosphorylation of Ser-271 in the activation loop [PMID:15024016]. Rather than relying on lipid-based recruitment, PKB is activated by calmodulin binding to a domain mapped within this same N-terminal region in a calcium-dependent manner, with calmodulin associating with PKB in intact parasites [PMID:16809343]. Phospholipase C acts upstream by triggering calcium release from intracellular stores, placing PKB within a PLC–Ca2+–calmodulin–PKB signaling cascade [PMID:16809343]. Beyond this activation logic, no physiological substrates or downstream effectors of PKB have been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Establishing whether P. falciparum encodes a functional PKB and how it achieves catalytic activation mattered because the parasite enzyme diverges structurally from its mammalian counterpart; the work showed a stage-specific kinase activated by activation-loop autophosphorylation rather than by canonical lipid signaling.","evidence":"In vitro biochemical and autophosphorylation assays with N-terminal domain dissection and inhibitor studies in P. falciparum","pmids":["15024016"],"confidence":"Medium","gaps":["No physiological substrate identified","Functional consequence of Ser-271 autophosphorylation in vivo not tested","Mechanism by which the N-terminal region represses catalysis not structurally defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"claim":"Because PKB lacks the PH domain used by mammalian orthologs for activation, the upstream input was unknown; identifying calmodulin as a calcium-dependent activator binding the N-terminal region defined a PLC–Ca2+–CaM–PKB cascade as the route to enzyme activation.","evidence":"CaM-binding domain mapping, co-immunoprecipitation of CaM with PKB in parasite lysates, calcium-dependent binding/activation assays, and PLC inhibitor experiments in P. falciparum","pmids":["16809343"],"confidence":"Medium","gaps":["Downstream substrates and biological output of activated PKB not identified","Findings from a single lab without independent replication","Physiological trigger for PLC activation in schizonts/merozoites not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The downstream branch of the pathway remains open: no physiological substrate, effector, or cellular process controlled by PKB has been established.","evidence":"No timeline discovery addresses PKB substrates or in vivo phenotype","pmids":[],"confidence":"Low","gaps":["No substrate identified","No genetic knockout or conditional depletion phenotype reported","Role in merozoite/schizont biology or invasion not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["CALMODULIN (CAM) — CALCIUM-DEPENDENT ACTIVATOR BINDING THE N-TERMINAL REGION OF PKB, ASSOCIATES IN INTACT PARASITES [#1]"],"other_free_text":["Expressed predominantly in schizonts and merozoites [#0]","Lacks the pleckstrin homology domain present in mammalian PKB [#0]","Catalytic activation requires autophosphorylation of Ser-271 in the activation loop [#0]","N-terminal region negatively regulates catalytic activity and contains the CaM-binding domain [#0, #1]","Phospholipase C acts upstream, releasing calcium from intracellular stores to drive CaM-mediated activation [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"15479470","id":"PMC_15479470","title":"Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote.","date":"2004","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/15479470","citation_count":421,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22127061","id":"PMC_22127061","title":"Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum.","date":"2011","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/22127061","citation_count":288,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"16809343","id":"PMC_16809343","title":"PfPKB, a protein kinase B-like enzyme from Plasmodium falciparum: II. Identification of calcium/calmodulin as its upstream activator and dissection of a novel signaling pathway.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16809343","citation_count":58,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15024016","id":"PMC_15024016","title":"PfPKB, a novel protein kinase B-like enzyme from Plasmodium falciparum: I. Identification, characterization, and possible role in parasite development.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15024016","citation_count":37,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PKB"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4631,"output_tokens":776,"usd":0.012767,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5442,"output_tokens":1829,"usd":0.036467,"stage2_stop_reason":"end_turn"},"total_usd":0.049234,"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\": \"PKB (PF3D7_1246900) was identified as a protein kinase B homologue in P. falciparum expressed mainly in schizonts and merozoites; it lacks a pleckstrin homology domain found in mammalian PKB. Biochemical studies demonstrated that its catalytic activation depends on autophosphorylation of a serine residue (Ser-271) in the activation loop, and that its unusual N-terminal region negatively regulates its catalytic activity.\",\n      \"method\": \"In vitro biochemical assays, autophosphorylation assays, N-terminal domain functional dissection, small-molecule inhibitor studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro enzymatic characterization and mutagenesis-level inference from a single lab with no independent replication reported\",\n      \"pmids\": [\"15024016\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Calmodulin (CaM) was identified as the upstream activator of PKB (PF3D7_1246900). A CaM-binding domain was mapped to the N-terminal region of PKB. CaM interacts with this domain in a calcium-dependent manner and activates PKB. CaM associates with PKB in intact parasites. Phospholipase C acts as an upstream regulator of this cascade by facilitating calcium release from intracellular stores, establishing a multicomponent PLC–Ca2+–CaM–PKB signaling pathway in P. falciparum.\",\n      \"method\": \"CaM-binding domain mapping, co-immunoprecipitation (CaM with PKB in parasite lysates), calcium-dependent binding/activation assays, phospholipase C inhibitor experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP showing CaM–PKB association in parasite, calcium-dependence assays, and pathway dissection with upstream inhibitor, all from a single lab\",\n      \"pmids\": [\"16809343\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PKB (PF3D7_1246900) is a P. falciparum serine/threonine kinase that lacks a pleckstrin homology domain, is expressed predominantly in schizonts and merozoites, undergoes autophosphorylation at Ser-271 in its activation loop for catalytic activation, is negatively regulated by its own N-terminal region, and is activated by calmodulin in a calcium-dependent manner downstream of phospholipase C-mediated calcium release from intracellular stores.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PKB (PF3D7_1246900) is a Plasmodium falciparum protein kinase B homologue that functions as a calcium-responsive serine/threonine kinase expressed predominantly in schizonts and merozoites [#0]. Unlike mammalian PKB, it lacks a pleckstrin homology domain; instead, its unusual N-terminal region serves a negative regulatory role, and its catalytic activation requires autophosphorylation of Ser-271 in the activation loop [#0]. Rather than relying on lipid-based recruitment, PKB is activated by calmodulin binding to a domain mapped within this same N-terminal region in a calcium-dependent manner, with calmodulin associating with PKB in intact parasites [#1]. Phospholipase C acts upstream by triggering calcium release from intracellular stores, placing PKB within a PLC\\u2013Ca2+\\u2013calmodulin\\u2013PKB signaling cascade [#1]. Beyond this activation logic, no physiological substrates or downstream effectors of PKB have been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing whether P. falciparum encodes a functional PKB and how it achieves catalytic activation mattered because the parasite enzyme diverges structurally from its mammalian counterpart; the work showed a stage-specific kinase activated by activation-loop autophosphorylation rather than by canonical lipid signaling.\",\n      \"evidence\": \"In vitro biochemical and autophosphorylation assays with N-terminal domain dissection and inhibitor studies in P. falciparum\",\n      \"pmids\": [\n        \"15024016\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No physiological substrate identified\",\n        \"Functional consequence of Ser-271 autophosphorylation in vivo not tested\",\n        \"Mechanism by which the N-terminal region represses catalysis not structurally defined\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Because PKB lacks the PH domain used by mammalian orthologs for activation, the upstream input was unknown; identifying calmodulin as a calcium-dependent activator binding the N-terminal region defined a PLC\\u2013Ca2+\\u2013CaM\\u2013PKB cascade as the route to enzyme activation.\",\n      \"evidence\": \"CaM-binding domain mapping, co-immunoprecipitation of CaM with PKB in parasite lysates, calcium-dependent binding/activation assays, and PLC inhibitor experiments in P. falciparum\",\n      \"pmids\": [\n        \"16809343\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream substrates and biological output of activated PKB not identified\",\n        \"Findings from a single lab without independent replication\",\n        \"Physiological trigger for PLC activation in schizonts/merozoites not defined\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The downstream branch of the pathway remains open: no physiological substrate, effector, or cellular process controlled by PKB has been established.\",\n      \"evidence\": \"No timeline discovery addresses PKB substrates or in vivo phenotype\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No substrate identified\",\n        \"No genetic knockout or conditional depletion phenotype reported\",\n        \"Role in merozoite/schizont biology or invasion not tested\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0004674\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      },\n      {\n        \"term_id\": \"GO:0046777\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005516\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0019722\",\n        \"supporting_discovery_ids\": [\n          1\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Calmodulin (CaM) \\u2014 calcium-dependent activator binding the N-terminal region of PKB, associates in intact parasites [#1]\"\n    ],\n    \"other_free_text\": [\n      \"Expressed predominantly in schizonts and merozoites [#0]\",\n      \"Lacks the pleckstrin homology domain present in mammalian PKB [#0]\",\n      \"Catalytic activation requires autophosphorylation of Ser-271 in the activation loop [#0]\",\n      \"N-terminal region negatively regulates catalytic activity and contains the CaM-binding domain [#0, #1]\",\n      \"Phospholipase C acts upstream, releasing calcium from intracellular stores to drive CaM-mediated activation [#1]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1246900","name":null,"product":"RAC-beta serine/threonine protein kinase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1460000","name":null,"product":"rac-beta serine/threonine protein kinase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1466600","name":null,"product":"RAC-beta serine/threonine protein kinase","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PKB","evaluation":null}