{"gene":"PF3D7_0806300","run_date":"2026-09-08T12:51:27","timeline":{"discoveries":[{"year":2019,"finding":"Genetic depletion of FLP (ferlin-like protein, PF3D7_0806300 ortholog) in sexual stages of P. berghei causes complete life cycle arrest in the mosquito: mature gametes form normally but remain trapped within the red blood cell, unable to egress. The egress defect is rescued by detergent-mediated membrane lysis, establishing FLP as a critical factor for membrane disruption during gamete egress. HA-tagged FLP localizes to intracellular speckles that relocalise to the cell periphery during gamete maturation, consistent with a role in calcium-dependent exocytosis.","method":"Genetic knockout (conditional depletion) in P. berghei sexual stages; HA-tagging and fluorescence microscopy for localization; detergent rescue experiment; mosquito infection assay","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined cellular phenotype (egress arrest), HA-tagging localization linked to functional stage, and detergent rescue as mechanistic control; single lab, single species","pmids":["30597708"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2010,"finding":"Phylogenetic analysis detected ferlin-like proteins in apicomplexan parasites including P. falciparum, placing PF3D7_0806300 within an ancient eukaryotic ferlin family defined by multiple tandem C2 domains, a C-terminal transmembrane domain, FerI, FerB structural motifs, and (in some members) a DysF domain. The C-terminal C2 domains (C2E and C2F) showed the highest sequence conservation and greatest conservation of putative calcium-binding residues, suggesting these are functionally critical.","method":"Phylogenetic analysis of genome sequences across representative eukaryotic phyla; domain architecture mapping","journal":"BMC evolutionary biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational/phylogenetic analysis only, no direct functional experiment performed on the P. falciparum protein","pmids":["20667140"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"FLP (PF3D7_0806300), the P. falciparum ferlin-like protein, is an ancient eukaryotic ferlin family member whose P. berghei ortholog localizes to intracellular vesicular speckles that redistribute to the cell periphery during gamete maturation, where it is required for calcium-dependent exocytosis mediating disruption of the red blood cell and parasitophorous vacuole membranes during gamete egress, as established by genetic knockout causing a rescuable egress block."},"narrative":{"mechanistic_narrative":"FLP (PF3D7_0806300) is the P. falciparum ferlin-like protein, a member of an ancient eukaryotic ferlin family characterized by multiple tandem C2 domains, a C-terminal transmembrane domain, and FerI/FerB structural motifs, with the C-terminal C2E and C2F domains showing the greatest conservation of putative calcium-binding residues [PMID:20667140]. Direct functional evidence derives from the P. berghei ortholog, where genetic depletion causes complete life cycle arrest in the mosquito: mature gametes form normally but remain trapped within the red blood cell, and the egress block is rescued by detergent-mediated membrane lysis, establishing FLP as required for the membrane disruption step of gamete egress [PMID:30597708]. Consistent with a role in calcium-dependent exocytosis, HA-tagged FLP localizes to intracellular speckles that relocalize to the cell periphery during gamete maturation [PMID:30597708]. No direct functional characterization of the P. falciparum PF3D7_0806300 protein itself has been reported in the available corpus beyond its phylogenetic placement [PMID:20667140]; the mechanistic role rests on the P. berghei ortholog.","teleology":[{"year":2010,"claim":"Whether apicomplexan parasites possess ferlin-family proteins was unresolved; phylogenetic analysis placed PF3D7_0806300 within an ancient eukaryotic ferlin family, defining its domain architecture and flagging the most conserved calcium-binding modules as candidate functional determinants.","evidence":"Phylogenetic analysis and domain architecture mapping across eukaryotic genomes","pmids":["20667140"],"confidence":"Low","gaps":["Computational/phylogenetic only — no direct functional experiment on the P. falciparum protein","Calcium binding by the C2E/C2F domains is inferred from sequence, not demonstrated","No localization or interaction data for PF3D7_0806300 itself"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"The cellular function of the ferlin-like protein was unknown; conditional depletion of the P. berghei ortholog showed it is required for gamete egress via membrane disruption, and its stage-dependent relocalization to the cell periphery linked it to calcium-dependent exocytosis.","evidence":"Conditional genetic knockout in P. berghei sexual stages with HA-tag fluorescence microscopy, detergent rescue, and mosquito infection assay","pmids":["30597708"],"confidence":"Medium","gaps":["Shown in the P. berghei ortholog, not directly in P. falciparum PF3D7_0806300","Molecular mechanism of membrane disruption and identity of any exocytic cargo or partners undefined","Whether the C2 domains bind calcium and drive the peripheral relocalization was not tested"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"Whether P. falciparum PF3D7_0806300 performs the egress function established for its P. berghei ortholog, and the molecular basis of its calcium-dependent membrane disruption activity, remain open.","evidence":"No direct functional study of PF3D7_0806300 in the available corpus","pmids":[],"confidence":"Low","gaps":["No direct P. falciparum functional or localization data","No identified binding partners, complex membership, or exocytic machinery link","No structural or biochemical demonstration of calcium binding"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["Ferlin family domain architecture: multiple tandem C2 domains, C-terminal transmembrane domain, FerI/FerB motifs; C2E and C2F are the most conserved and carry putative calcium-binding residues [#1].","Functional evidence derives from the P. berghei ortholog: knockout blocks gamete egress at the membrane-disruption step, rescued by detergent lysis [#0].","No direct experimental characterization of P. falciparum PF3D7_0806300 beyond phylogenetic placement in the available corpus."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"20667140","id":"PMC_20667140","title":"Phylogenetic analysis of ferlin genes reveals ancient eukaryotic origins.","date":"2010","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/20667140","citation_count":50,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30597708","id":"PMC_30597708","title":"Transmission of the malaria parasite requires ferlin for gamete egress from the red blood cell.","date":"2019","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30597708","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["FLP"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31321598","id":"PMC_31321598","title":"Infectivity and Screening of Anti-piperaquine Genes in Mice Infected with Piperaquine-Sensitive and Piperaquine-Resistant Plasmodium berghei.","date":"2019","source":"Acta parasitologica","url":"https://pubmed.ncbi.nlm.nih.gov/31321598","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ferlin-like protein"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4552,"output_tokens":784,"usd":0.012708,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5457,"output_tokens":1815,"usd":0.03633,"stage2_stop_reason":"end_turn"},"total_usd":0.049038,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic depletion of FLP (ferlin-like protein, PF3D7_0806300 ortholog) in sexual stages of P. berghei causes complete life cycle arrest in the mosquito: mature gametes form normally but remain trapped within the red blood cell, unable to egress. The egress defect is rescued by detergent-mediated membrane lysis, establishing FLP as a critical factor for membrane disruption during gamete egress. HA-tagged FLP localizes to intracellular speckles that relocalise to the cell periphery during gamete maturation, consistent with a role in calcium-dependent exocytosis.\",\n      \"method\": \"Genetic knockout (conditional depletion) in P. berghei sexual stages; HA-tagging and fluorescence microscopy for localization; detergent rescue experiment; mosquito infection assay\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined cellular phenotype (egress arrest), HA-tagging localization linked to functional stage, and detergent rescue as mechanistic control; single lab, single species\",\n      \"pmids\": [\"30597708\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Phylogenetic analysis detected ferlin-like proteins in apicomplexan parasites including P. falciparum, placing PF3D7_0806300 within an ancient eukaryotic ferlin family defined by multiple tandem C2 domains, a C-terminal transmembrane domain, FerI, FerB structural motifs, and (in some members) a DysF domain. The C-terminal C2 domains (C2E and C2F) showed the highest sequence conservation and greatest conservation of putative calcium-binding residues, suggesting these are functionally critical.\",\n      \"method\": \"Phylogenetic analysis of genome sequences across representative eukaryotic phyla; domain architecture mapping\",\n      \"journal\": \"BMC evolutionary biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational/phylogenetic analysis only, no direct functional experiment performed on the P. falciparum protein\",\n      \"pmids\": [\"20667140\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"FLP (PF3D7_0806300), the P. falciparum ferlin-like protein, is an ancient eukaryotic ferlin family member whose P. berghei ortholog localizes to intracellular vesicular speckles that redistribute to the cell periphery during gamete maturation, where it is required for calcium-dependent exocytosis mediating disruption of the red blood cell and parasitophorous vacuole membranes during gamete egress, as established by genetic knockout causing a rescuable egress block.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FLP (PF3D7_0806300) is the P. falciparum ferlin-like protein, a member of an ancient eukaryotic ferlin family characterized by multiple tandem C2 domains, a C-terminal transmembrane domain, and FerI/FerB structural motifs, with the C-terminal C2E and C2F domains showing the greatest conservation of putative calcium-binding residues [#1]. Direct functional evidence derives from the P. berghei ortholog, where genetic depletion causes complete life cycle arrest in the mosquito: mature gametes form normally but remain trapped within the red blood cell, and the egress block is rescued by detergent-mediated membrane lysis, establishing FLP as required for the membrane disruption step of gamete egress [#0]. Consistent with a role in calcium-dependent exocytosis, HA-tagged FLP localizes to intracellular speckles that relocalize to the cell periphery during gamete maturation [#0]. No direct functional characterization of the P. falciparum PF3D7_0806300 protein itself has been reported in the available corpus beyond its phylogenetic placement [#1]; the mechanistic role rests on the P. berghei ortholog.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether apicomplexan parasites possess ferlin-family proteins was unresolved; phylogenetic analysis placed PF3D7_0806300 within an ancient eukaryotic ferlin family, defining its domain architecture and flagging the most conserved calcium-binding modules as candidate functional determinants.\",\n      \"evidence\": \"Phylogenetic analysis and domain architecture mapping across eukaryotic genomes\",\n      \"pmids\": [\"20667140\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational/phylogenetic only \\u2014 no direct functional experiment on the P. falciparum protein\",\n        \"Calcium binding by the C2E/C2F domains is inferred from sequence, not demonstrated\",\n        \"No localization or interaction data for PF3D7_0806300 itself\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The cellular function of the ferlin-like protein was unknown; conditional depletion of the P. berghei ortholog showed it is required for gamete egress via membrane disruption, and its stage-dependent relocalization to the cell periphery linked it to calcium-dependent exocytosis.\",\n      \"evidence\": \"Conditional genetic knockout in P. berghei sexual stages with HA-tag fluorescence microscopy, detergent rescue, and mosquito infection assay\",\n      \"pmids\": [\"30597708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Shown in the P. berghei ortholog, not directly in P. falciparum PF3D7_0806300\",\n        \"Molecular mechanism of membrane disruption and identity of any exocytic cargo or partners undefined\",\n        \"Whether the C2 domains bind calcium and drive the peripheral relocalization was not tested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether P. falciparum PF3D7_0806300 performs the egress function established for its P. berghei ortholog, and the molecular basis of its calcium-dependent membrane disruption activity, remain open.\",\n      \"evidence\": \"No direct functional study of PF3D7_0806300 in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct P. falciparum functional or localization data\",\n        \"No identified binding partners, complex membership, or exocytic machinery link\",\n        \"No structural or biochemical demonstration of calcium binding\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005544\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0071944\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006887\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0035847\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Ferlin family domain architecture: multiple tandem C2 domains, C-terminal transmembrane domain, FerI/FerB motifs; C2E and C2F are the most conserved and carry putative calcium-binding residues [#1].\",\n      \"Functional evidence derives from the P. berghei ortholog: knockout blocks gamete egress at the membrane-disruption step, rescued by detergent lysis [#0].\",\n      \"No direct experimental characterization of P. falciparum PF3D7_0806300 beyond phylogenetic placement in the available corpus.\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0806300","name":null,"product":"ferlin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1224400","name":null,"product":"ferlin-like protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0112600","name":null,"product":"ferlin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"FLP","evaluation":null}