{"gene":"PF3D7_1337800","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2010,"finding":"CDPK5 (PfCDPK5) is expressed in invasive merozoite forms and is essential for parasite egress from erythrocytes; conditional knockdown results in arrest as mature schizonts with intact membranes despite normal maturation of egress proteases and invasion ligands. Merozoites physically released from stalled schizonts retain invasion competence, separating egress and invasion pathways. The egress arrest is downstream of PfPKG function and independent of protease processing.","method":"Conditional knockdown with specific phenotypic readout (schizont arrest, membrane integrity assay, physical release rescue); genetic epistasis with PKG inhibitor","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional knockdown with multiple orthogonal phenotypic readouts, epistasis experiment placing CDPK5 downstream of PKG, independently replicated in later work","pmids":["20466936"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"CDPK5 colocalizes with micronemes in P. falciparum schizonts and is required for microneme discharge; failure of microneme release is the molecular mechanism underlying the egress block observed upon CDPK5 knockdown. CDPK5 cooperates with PfPKG to fully activate the protease cascade critical for egress, and hyperactivation of PfPKG can overcome the CDPK5-dependent arrest, restoring microneme release.","method":"Conditional knockdown + colocalization (live imaging/IFA with microneme markers) + rescue by PKG hyperactivation + physical disruption rescue assay; genetic epistasis with PKG","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, functional knockdown, epistasis/rescue), rigorous controls, defines molecular mechanism","pmids":["29487234"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Phosphoproteomic profiling of CDPK5-deficient late schizonts identified 58 phosphorylation sites on 50 proteins significantly reduced in the absence of CDPK5, including PfNPT1 (a novel putative transporter localized to the parasite plasma membrane) as a potential CDPK5 substrate. Gene ontology analysis of affected proteins showed enrichment for transmembrane/membrane-associated proteins and transport activity.","method":"Label-free quantitative phosphoproteomics (mass spectrometry) on synchronized CDPK5 conditional-knockdown parasites; subcellular localization of PfNPT1 by fluorescence microscopy","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative phosphoproteomics with conditional knockdown is rigorous; PfNPT1 substrate relationship established by reduction in phosphorylation but not yet confirmed by in vitro kinase assay","pmids":["31915223"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"Mutations in CDPK5 (together with PfATP4) are necessary to confer full resistance to pyrazoleamide antimalarial compounds, implicating CDPK5 in the pathway targeted by these drugs; whole-genome sequencing of resistant parasites and gene-transfer experiments established this genotype–resistance relationship.","method":"Selection of drug-resistant parasites, whole-genome sequencing, gene transfer","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene-transfer and resistance genetics establish CDPK5 involvement, but the precise mechanistic role of the mutation in drug resistance is not fully resolved in the abstract","pmids":["25422853"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"In P. berghei, CDPK5 is required for optimal sporozoite motility and hepatocyte invasion; elevated cGMP can compensate for loss of CDPK5 during sporozoite invasion. CDPK5 expression is downregulated after sporozoite invasion but reappears in late liver stages and merosomes; depletion of CDPK5 in liver stages/merosomes implicates it in merosome formation/release and delays initiation of the erythrocytic cycle.","method":"Genetic depletion (conditional knockdown) of CDPK5 in P. berghei sporozoites and liver stages; motility assays; cGMP rescue experiments; immunofluorescence for stage-specific expression","journal":"PLoS Pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean depletion with specific phenotypic readouts at multiple life-cycle stages and pharmacological rescue, single lab","pmids":["32866196"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"CDPK5 is a calcium-dependent protein kinase that acts downstream of cGMP-dependent protein kinase (PKG) to drive microneme discharge and erythrocyte egress in P. falciparum blood stages, with its phosphoproteomic substrates including plasma-membrane transporter PfNPT1; in P. berghei it additionally supports sporozoite motility, hepatocyte invasion, and merosome release during pre-erythrocytic stages."},"narrative":{"mechanistic_narrative":"CDPK5 (PF3D7_1337800) is a calcium-dependent protein kinase that drives egress of Plasmodium from its host cell by triggering microneme discharge, acting downstream of and in cooperation with cGMP-dependent protein kinase (PKG) [PMID:20466936, PMID:29487234]. In P. falciparum, CDPK5 is expressed in invasive merozoites and is essential for erythrocyte egress: conditional knockdown arrests parasites as mature schizonts with intact membranes, even though egress proteases and invasion ligands mature normally, and merozoites physically freed from stalled schizonts remain invasion-competent, functionally separating egress from invasion [PMID:20466936]. Mechanistically, CDPK5 colocalizes with micronemes in schizonts and its loss blocks microneme discharge; hyperactivation of PfPKG bypasses the CDPK5-dependent arrest and restores microneme release, placing CDPK5 within the PKG-coordinated protease cascade that executes egress [PMID:29487234]. Phosphoproteomics of CDPK5-deficient schizonts identified 58 reduced phosphosites on 50 proteins enriched for transmembrane and transport functions, including the plasma-membrane transporter PfNPT1 as a candidate substrate [PMID:31915223]. In P. berghei, CDPK5 additionally supports sporozoite motility, hepatocyte invasion, and merosome formation/release, with elevated cGMP compensating for its loss during sporozoite invasion [PMID:32866196]. CDPK5 mutations, together with PfATP4 mutations, confer full resistance to pyrazoleamide antimalarials, implicating it in the targeted pathway [PMID:25422853].","teleology":[{"year":2010,"claim":"Establishing whether CDPK5 has an essential and stage-specific role addressed whether the kinase controls a discrete step of the blood-stage cycle rather than general viability.","evidence":"Conditional knockdown in P. falciparum with schizont-arrest and membrane-integrity readouts, plus physical-release rescue and PKG-inhibitor epistasis","pmids":["20466936"],"confidence":"High","gaps":["The direct molecular event blocked by CDPK5 loss was not identified","Kinase substrates were unknown","Relationship to PKG was defined by epistasis but not mechanistically"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Linking CDPK5 to pyrazoleamide resistance placed the kinase within a druggable pathway and connected it to PfATP4 biology.","evidence":"Selection of resistant P. falciparum, whole-genome sequencing, and gene-transfer experiments showing CDPK5 plus PfATP4 mutations confer full resistance","pmids":["25422853"],"confidence":"Medium","gaps":["The mechanistic role of the CDPK5 mutation in resistance is unresolved","Whether resistance reflects altered kinase activity is unknown","Direct interaction between CDPK5 and PfATP4 not demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Identifying microneme discharge as the CDPK5-dependent step defined the molecular mechanism of the egress block and positioned CDPK5 relative to PKG.","evidence":"Conditional knockdown with microneme-marker colocalization, PKG-hyperactivation rescue, and physical-disruption rescue in P. falciparum schizonts","pmids":["29487234"],"confidence":"High","gaps":["Direct substrates mediating microneme discharge not identified","How CDPK5 and PKG signals converge biochemically unknown","Calcium signal activating CDPK5 not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Phosphoproteomic profiling began defining the CDPK5 substrate landscape, nominating membrane and transport proteins including PfNPT1.","evidence":"Label-free quantitative phosphoproteomics on CDPK5 conditional-knockdown P. falciparum schizonts, with fluorescence localization of PfNPT1","pmids":["31915223"],"confidence":"Medium","gaps":["PfNPT1 substrate relationship not confirmed by in vitro kinase assay","Reduced phosphosites may be indirect","Functional link between candidate substrates and microneme discharge not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"Extending analysis to pre-erythrocytic stages showed CDPK5 function is not restricted to blood-stage egress but recurs across the life cycle.","evidence":"Conditional depletion in P. berghei sporozoites and liver stages with motility assays, cGMP rescue, and stage-specific immunofluorescence","pmids":["32866196"],"confidence":"Medium","gaps":["Substrates in sporozoite/liver stages not identified","Whether the merosome-release role uses the same microneme mechanism as blood-stage egress unknown","Single-lab evidence"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"How CDPK5 is activated by calcium and which direct substrates couple its kinase activity to microneme discharge remain the central open questions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro-validated direct substrate","Mechanism of biochemical convergence with PKG unresolved","Upstream calcium signal and regulation undefined"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFPKG (CGMP-DEPENDENT PROTEIN KINASE; FUNCTIONAL/EPISTATIC COOPERATION) [#0, #1]","PFNPT1 (CANDIDATE SUBSTRATE) [#2]","PFATP4 (CO-MUTATED IN PYRAZOLEAMIDE RESISTANCE) [#3]"],"other_free_text":["Essential for P. falciparum erythrocyte egress via microneme discharge, acting downstream of PfPKG; PKG hyperactivation bypasses CDPK5-dependent arrest [#0, #1].","Egress function is separable from invasion competence of merozoites [#0].","In P. berghei, required for sporozoite motility, hepatocyte invasion, and merosome formation/release; elevated cGMP compensates for its loss during sporozoite invasion [#4].","CDPK5 mutations with PfATP4 confer full pyrazoleamide resistance [#3]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"20466936","id":"PMC_20466936","title":"A plant-like kinase in Plasmodium falciparum regulates parasite egress from erythrocytes.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20466936","citation_count":245,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfCDPK5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25422853","id":"PMC_25422853","title":"Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25422853","citation_count":104,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfCDPK5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29487234","id":"PMC_29487234","title":"Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in Plasmodium falciparum.","date":"2018","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/29487234","citation_count":64,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["calcium-dependent protein kinase 5","PfCDPK5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"27923926","id":"PMC_27923926","title":"Reduced Activity of Mutant Calcium-Dependent Protein Kinase 1 Is Compensated in Plasmodium falciparum through the Action of Protein Kinase G.","date":"2016","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/27923926","citation_count":37,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDPK5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32866196","id":"PMC_32866196","title":"Overlapping and distinct roles of CDPK family members in the pre-erythrocytic stages of the rodent malaria parasite, Plasmodium berghei.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/32866196","citation_count":22,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDPK5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31915223","id":"PMC_31915223","title":"Influence of Plasmodium falciparum Calcium-Dependent Protein Kinase 5 (PfCDPK5) on the Late Schizont Stage Phosphoproteome.","date":"2020","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/31915223","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["calcium-dependent protein kinase 5","PfCDPK5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30409756","id":"PMC_30409756","title":"In silico analysis of plasmodium falciparum CDPK5 protein through molecular modeling, docking and dynamics.","date":"2018","source":"Journal of theoretical biology","url":"https://pubmed.ncbi.nlm.nih.gov/30409756","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDPK5","calcium-dependent protein kinase 5","PfCDPK5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6848,"output_tokens":1575,"usd":0.022084,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6647,"output_tokens":2622,"usd":0.049392,"stage2_stop_reason":"end_turn"},"total_usd":0.071476,"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\": 2010,\n      \"finding\": \"CDPK5 (PfCDPK5) is expressed in invasive merozoite forms and is essential for parasite egress from erythrocytes; conditional knockdown results in arrest as mature schizonts with intact membranes despite normal maturation of egress proteases and invasion ligands. Merozoites physically released from stalled schizonts retain invasion competence, separating egress and invasion pathways. The egress arrest is downstream of PfPKG function and independent of protease processing.\",\n      \"method\": \"Conditional knockdown with specific phenotypic readout (schizont arrest, membrane integrity assay, physical release rescue); genetic epistasis with PKG inhibitor\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional knockdown with multiple orthogonal phenotypic readouts, epistasis experiment placing CDPK5 downstream of PKG, independently replicated in later work\",\n      \"pmids\": [\"20466936\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDPK5 colocalizes with micronemes in P. falciparum schizonts and is required for microneme discharge; failure of microneme release is the molecular mechanism underlying the egress block observed upon CDPK5 knockdown. CDPK5 cooperates with PfPKG to fully activate the protease cascade critical for egress, and hyperactivation of PfPKG can overcome the CDPK5-dependent arrest, restoring microneme release.\",\n      \"method\": \"Conditional knockdown + colocalization (live imaging/IFA with microneme markers) + rescue by PKG hyperactivation + physical disruption rescue assay; genetic epistasis with PKG\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, functional knockdown, epistasis/rescue), rigorous controls, defines molecular mechanism\",\n      \"pmids\": [\"29487234\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Phosphoproteomic profiling of CDPK5-deficient late schizonts identified 58 phosphorylation sites on 50 proteins significantly reduced in the absence of CDPK5, including PfNPT1 (a novel putative transporter localized to the parasite plasma membrane) as a potential CDPK5 substrate. Gene ontology analysis of affected proteins showed enrichment for transmembrane/membrane-associated proteins and transport activity.\",\n      \"method\": \"Label-free quantitative phosphoproteomics (mass spectrometry) on synchronized CDPK5 conditional-knockdown parasites; subcellular localization of PfNPT1 by fluorescence microscopy\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative phosphoproteomics with conditional knockdown is rigorous; PfNPT1 substrate relationship established by reduction in phosphorylation but not yet confirmed by in vitro kinase assay\",\n      \"pmids\": [\"31915223\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutations in CDPK5 (together with PfATP4) are necessary to confer full resistance to pyrazoleamide antimalarial compounds, implicating CDPK5 in the pathway targeted by these drugs; whole-genome sequencing of resistant parasites and gene-transfer experiments established this genotype–resistance relationship.\",\n      \"method\": \"Selection of drug-resistant parasites, whole-genome sequencing, gene transfer\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene-transfer and resistance genetics establish CDPK5 involvement, but the precise mechanistic role of the mutation in drug resistance is not fully resolved in the abstract\",\n      \"pmids\": [\"25422853\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In P. berghei, CDPK5 is required for optimal sporozoite motility and hepatocyte invasion; elevated cGMP can compensate for loss of CDPK5 during sporozoite invasion. CDPK5 expression is downregulated after sporozoite invasion but reappears in late liver stages and merosomes; depletion of CDPK5 in liver stages/merosomes implicates it in merosome formation/release and delays initiation of the erythrocytic cycle.\",\n      \"method\": \"Genetic depletion (conditional knockdown) of CDPK5 in P. berghei sporozoites and liver stages; motility assays; cGMP rescue experiments; immunofluorescence for stage-specific expression\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean depletion with specific phenotypic readouts at multiple life-cycle stages and pharmacological rescue, single lab\",\n      \"pmids\": [\"32866196\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"CDPK5 is a calcium-dependent protein kinase that acts downstream of cGMP-dependent protein kinase (PKG) to drive microneme discharge and erythrocyte egress in P. falciparum blood stages, with its phosphoproteomic substrates including plasma-membrane transporter PfNPT1; in P. berghei it additionally supports sporozoite motility, hepatocyte invasion, and merosome release during pre-erythrocytic stages.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDPK5 (PF3D7_1337800) is a calcium-dependent protein kinase that drives egress of Plasmodium from its host cell by triggering microneme discharge, acting downstream of and in cooperation with cGMP-dependent protein kinase (PKG) [#0, #1]. In P. falciparum, CDPK5 is expressed in invasive merozoites and is essential for erythrocyte egress: conditional knockdown arrests parasites as mature schizonts with intact membranes, even though egress proteases and invasion ligands mature normally, and merozoites physically freed from stalled schizonts remain invasion-competent, functionally separating egress from invasion [#0]. Mechanistically, CDPK5 colocalizes with micronemes in schizonts and its loss blocks microneme discharge; hyperactivation of PfPKG bypasses the CDPK5-dependent arrest and restores microneme release, placing CDPK5 within the PKG-coordinated protease cascade that executes egress [#1]. Phosphoproteomics of CDPK5-deficient schizonts identified 58 reduced phosphosites on 50 proteins enriched for transmembrane and transport functions, including the plasma-membrane transporter PfNPT1 as a candidate substrate [#2]. In P. berghei, CDPK5 additionally supports sporozoite motility, hepatocyte invasion, and merosome formation/release, with elevated cGMP compensating for its loss during sporozoite invasion [#4]. CDPK5 mutations, together with PfATP4 mutations, confer full resistance to pyrazoleamide antimalarials, implicating it in the targeted pathway [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing whether CDPK5 has an essential and stage-specific role addressed whether the kinase controls a discrete step of the blood-stage cycle rather than general viability.\",\n      \"evidence\": \"Conditional knockdown in P. falciparum with schizont-arrest and membrane-integrity readouts, plus physical-release rescue and PKG-inhibitor epistasis\",\n      \"pmids\": [\"20466936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The direct molecular event blocked by CDPK5 loss was not identified\", \"Kinase substrates were unknown\", \"Relationship to PKG was defined by epistasis but not mechanistically\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking CDPK5 to pyrazoleamide resistance placed the kinase within a druggable pathway and connected it to PfATP4 biology.\",\n      \"evidence\": \"Selection of resistant P. falciparum, whole-genome sequencing, and gene-transfer experiments showing CDPK5 plus PfATP4 mutations confer full resistance\",\n      \"pmids\": [\"25422853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The mechanistic role of the CDPK5 mutation in resistance is unresolved\", \"Whether resistance reflects altered kinase activity is unknown\", \"Direct interaction between CDPK5 and PfATP4 not demonstrated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying microneme discharge as the CDPK5-dependent step defined the molecular mechanism of the egress block and positioned CDPK5 relative to PKG.\",\n      \"evidence\": \"Conditional knockdown with microneme-marker colocalization, PKG-hyperactivation rescue, and physical-disruption rescue in P. falciparum schizonts\",\n      \"pmids\": [\"29487234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates mediating microneme discharge not identified\", \"How CDPK5 and PKG signals converge biochemically unknown\", \"Calcium signal activating CDPK5 not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Phosphoproteomic profiling began defining the CDPK5 substrate landscape, nominating membrane and transport proteins including PfNPT1.\",\n      \"evidence\": \"Label-free quantitative phosphoproteomics on CDPK5 conditional-knockdown P. falciparum schizonts, with fluorescence localization of PfNPT1\",\n      \"pmids\": [\"31915223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PfNPT1 substrate relationship not confirmed by in vitro kinase assay\", \"Reduced phosphosites may be indirect\", \"Functional link between candidate substrates and microneme discharge not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extending analysis to pre-erythrocytic stages showed CDPK5 function is not restricted to blood-stage egress but recurs across the life cycle.\",\n      \"evidence\": \"Conditional depletion in P. berghei sporozoites and liver stages with motility assays, cGMP rescue, and stage-specific immunofluorescence\",\n      \"pmids\": [\"32866196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrates in sporozoite/liver stages not identified\", \"Whether the merosome-release role uses the same microneme mechanism as blood-stage egress unknown\", \"Single-lab evidence\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDPK5 is activated by calcium and which direct substrates couple its kinase activity to microneme discharge remain the central open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro-validated direct substrate\", \"Mechanism of biochemical convergence with PKG unresolved\", \"Upstream calcium signal and regulation undefined\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0004683\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0035891\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfPKG (cGMP-dependent protein kinase; functional/epistatic cooperation) [#0, #1]\",\n      \"PfNPT1 (candidate substrate) [#2]\",\n      \"PfATP4 (co-mutated in pyrazoleamide resistance) [#3]\"\n    ],\n    \"other_free_text\": [\n      \"Essential for P. falciparum erythrocyte egress via microneme discharge, acting downstream of PfPKG; PKG hyperactivation bypasses CDPK5-dependent arrest [#0, #1].\",\n      \"Egress function is separable from invasion competence of merozoites [#0].\",\n      \"In P. berghei, required for sporozoite motility, hepatocyte invasion, and merosome formation/release; elevated cGMP compensates for its loss during sporozoite invasion [#4].\",\n      \"CDPK5 mutations with PfATP4 confer full pyrazoleamide resistance [#3].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1337800","name":null,"product":"calcium-dependent protein kinase 5","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1351500","name":null,"product":"calcium-dependent protein kinase 5","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1263500","name":null,"product":"calcium-dependent protein kinase 5, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"CDPK5","evaluation":null}