{"gene":"PF3D7_1029400","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2022,"finding":"CDC50C (PF3D7_1029400) is expressed in asexual blood stages of P. falciparum and is a direct binding partner of the putative P4-ATPase phospholipid-transporting ATPase 2 (ATP2), forming a CDC50C–ATP2 complex.","method":"Gene tagging and co-immunoprecipitation / conditional gene disruption","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene tagging plus binding-partner identification in P. falciparum, single lab with two complementary approaches (expression tagging and interaction assay)","pmids":["35862778"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"CDC50C (PF3D7_1029400) is essential for intraerythrocytic blood-stage trophozoite maturation in P. falciparum; conditional disruption of CDC50C arrests parasite development at the trophozoite stage.","method":"Conditional gene disruption (inducible knockdown) with phenotypic readout of parasite developmental progression","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockdown with defined developmental phenotype, single lab","pmids":["35862778"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"The CDC50C–ATP2 complex influences parasite endocytosis of host cell hemoglobin and consequently hemozoin formation in P. falciparum blood stages.","method":"Conditional gene disruption of CDC50C followed by measurement of hemoglobin uptake and hemozoin formation","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular readouts (endocytosis, hemozoin), single lab","pmids":["35862778"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"In P. yoelii, CDC50C co-localizes and physically interacts with the P4-ATPase ATP7 on the ookinete plasma membrane, acting as the flippase cofactor; depletion of CDC50C phenocopies ATP7 deficiency, blocking mosquito midgut epithelium traversal and parasite transmission.","method":"Co-localization imaging, co-immunoprecipitation/interaction assay, and conditional depletion (AID system) with phenotypic readout of mosquito infection","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-localization plus interaction plus genetic phenocopy in P. yoelii, single lab with multiple orthogonal approaches","pmids":["34301597"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2020,"finding":"In P. yoelii, CDC50C tagged with the auxin-inducible degron (AID) motif is efficiently degraded upon auxin treatment in asexual schizont and sexual gametocyte stages (using the eef1a-Tir1 background) and in ookinetes (using the soap-Tir1 background), validating its conditional depletion as a functional tool.","method":"CRISPR/Cas9-mediated AID tagging with auxin-induced proteasomal degradation and Western blot/immunofluorescence confirmation","journal":"Molecular and biochemical parasitology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — demonstration of conditional depletion system for CDC50C in P. yoelii, single lab, primarily a tool-development paper with limited mechanistic follow-up reported","pmids":["33307135"],"is_preprint":false,"attribution":[{"species":"Plasmodium yoelii","strain":""}]}],"current_model":"CDC50C (PF3D7_1029400) is a P4-ATPase chaperone that forms distinct complexes with different P4-ATPase partners depending on context: in P. falciparum asexual blood stages it partners with ATP2 in a complex that is essential for trophozoite maturation and influences hemoglobin endocytosis and hemozoin formation, while in P. yoelii ookinetes it interacts with ATP7 on the plasma membrane to enable phosphatidylcholine flipping and midgut traversal required for mosquito transmission."},"narrative":{"mechanistic_narrative":"CDC50C (PF3D7_1029400) is a P4-ATPase chaperone/flippase cofactor that partners with different P4-ATPase subunits in a stage- and species-dependent manner to support Plasmodium development and mosquito transmission [PMID:35862778, PMID:34301597]. In P. falciparum asexual blood stages, CDC50C is a direct binding partner of the putative phospholipid-transporting P4-ATPase ATP2, forming a CDC50C–ATP2 complex that is essential for intraerythrocytic development: conditional disruption of CDC50C arrests parasites at the trophozoite stage and impairs endocytosis of host hemoglobin and downstream hemozoin formation [PMID:35862778]. In P. yoelii ookinetes, CDC50C instead co-localizes and physically interacts with the P4-ATPase ATP7 on the plasma membrane and acts as its flippase cofactor, with depletion phenocopying ATP7 deficiency and blocking mosquito midgut traversal and transmission [PMID:34301597]. Beyond its role as a P4-ATPase partner in these two contexts, no additional catalytic or structural mechanism for CDC50C has been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Establishing a controllable way to deplete CDC50C was a prerequisite for probing its function, since the protein's essentiality could otherwise preclude genetic analysis.","evidence":"CRISPR/Cas9 AID tagging with auxin-induced degradation confirmed by Western blot/immunofluorescence across asexual, gametocyte, and ookinete stages in P. yoelii","pmids":["33307135"],"confidence":"Low","gaps":["Primarily a tool-development study with limited mechanistic follow-up reported here","Does not itself assign a molecular function to CDC50C","No partner or substrate identified in this work"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2021,"claim":"Whether CDC50C acts as a dedicated cofactor for a specific P4-ATPase in transmission stages was resolved by showing it partners with ATP7 on the ookinete plasma membrane.","evidence":"Co-localization imaging, co-immunoprecipitation, and AID-mediated conditional depletion with mosquito-infection phenotyping in P. yoelii","pmids":["34301597"],"confidence":"Medium","gaps":["Direct biochemical demonstration of lipid-flipping activity by the CDC50C–ATP7 complex not shown","Whether CDC50C partners with additional P4-ATPases in ookinetes not resolved","Species conservation of the ATP7 partnership to P. falciparum not tested"],"attribution":[{"species":"Plasmodium yoelii","strain":""}]},{"year":2022,"claim":"The blood-stage function of CDC50C was defined by identifying ATP2 as its partner and linking the complex to trophozoite maturation, hemoglobin endocytosis, and hemozoin formation.","evidence":"Gene tagging, co-immunoprecipitation, and conditional gene disruption with developmental, hemoglobin-uptake, and hemozoin readouts in P. falciparum","pmids":["35862778"],"confidence":"Medium","gaps":["Direct enzymatic/flippase activity of the CDC50C–ATP2 complex not demonstrated biochemically","Mechanistic link between phospholipid transport and hemoglobin endocytosis not resolved","Single-lab characterization"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"It remains unknown whether CDC50C directly confers or regulates phospholipid-flipping catalysis and how its partner choice (ATP2 vs ATP7) is determined across stages and species.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CDC50C or its P4-ATPase complexes","No reconstituted biochemical assay of flippase activity","Rules governing partner specificity across life-cycle stages unresolved"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["CDC50C–ATP2 complex (P. falciparum)","CDC50C–ATP7 complex (P. yoelii)"],"partners":["ATP2 (P4-ATPASE, P. FALCIPARUM)","ATP7 (P4-ATPASE, P. YOELII)"],"other_free_text":["Essential for P. falciparum intraerythrocytic trophozoite maturation [#1]","Required for P. yoelii mosquito midgut traversal and transmission [#3]","Conditional depletion validated via auxin-inducible degron in P. yoelii [#4]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"35862778","id":"PMC_35862778","title":"CDC50 Orthologues in Plasmodium falciparum Have Distinct Roles in Merozoite Egress and Trophozoite Maturation.","date":"2022","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/35862778","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50C"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34301597","id":"PMC_34301597","title":"A malaria parasite phospholipid flippase safeguards midgut traversal of ookinetes for mosquito transmission.","date":"2021","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/34301597","citation_count":14,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50C"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33307135","id":"PMC_33307135","title":"Generation of Plasmodium yoelii malaria parasite for conditional degradation of proteins.","date":"2020","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/33307135","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50C"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4408,"output_tokens":1334,"usd":0.016617,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6247,"output_tokens":2012,"usd":0.040767,"stage2_stop_reason":"end_turn"},"total_usd":0.057384,"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\": 2022,\n      \"finding\": \"CDC50C (PF3D7_1029400) is expressed in asexual blood stages of P. falciparum and is a direct binding partner of the putative P4-ATPase phospholipid-transporting ATPase 2 (ATP2), forming a CDC50C–ATP2 complex.\",\n      \"method\": \"Gene tagging and co-immunoprecipitation / conditional gene disruption\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene tagging plus binding-partner identification in P. falciparum, single lab with two complementary approaches (expression tagging and interaction assay)\",\n      \"pmids\": [\"35862778\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDC50C (PF3D7_1029400) is essential for intraerythrocytic blood-stage trophozoite maturation in P. falciparum; conditional disruption of CDC50C arrests parasite development at the trophozoite stage.\",\n      \"method\": \"Conditional gene disruption (inducible knockdown) with phenotypic readout of parasite developmental progression\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockdown with defined developmental phenotype, single lab\",\n      \"pmids\": [\"35862778\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CDC50C–ATP2 complex influences parasite endocytosis of host cell hemoglobin and consequently hemozoin formation in P. falciparum blood stages.\",\n      \"method\": \"Conditional gene disruption of CDC50C followed by measurement of hemoglobin uptake and hemozoin formation\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular readouts (endocytosis, hemozoin), single lab\",\n      \"pmids\": [\"35862778\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In P. yoelii, CDC50C co-localizes and physically interacts with the P4-ATPase ATP7 on the ookinete plasma membrane, acting as the flippase cofactor; depletion of CDC50C phenocopies ATP7 deficiency, blocking mosquito midgut epithelium traversal and parasite transmission.\",\n      \"method\": \"Co-localization imaging, co-immunoprecipitation/interaction assay, and conditional depletion (AID system) with phenotypic readout of mosquito infection\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-localization plus interaction plus genetic phenocopy in P. yoelii, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34301597\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In P. yoelii, CDC50C tagged with the auxin-inducible degron (AID) motif is efficiently degraded upon auxin treatment in asexual schizont and sexual gametocyte stages (using the eef1a-Tir1 background) and in ookinetes (using the soap-Tir1 background), validating its conditional depletion as a functional tool.\",\n      \"method\": \"CRISPR/Cas9-mediated AID tagging with auxin-induced proteasomal degradation and Western blot/immunofluorescence confirmation\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — demonstration of conditional depletion system for CDC50C in P. yoelii, single lab, primarily a tool-development paper with limited mechanistic follow-up reported\",\n      \"pmids\": [\"33307135\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"CDC50C (PF3D7_1029400) is a P4-ATPase chaperone that forms distinct complexes with different P4-ATPase partners depending on context: in P. falciparum asexual blood stages it partners with ATP2 in a complex that is essential for trophozoite maturation and influences hemoglobin endocytosis and hemozoin formation, while in P. yoelii ookinetes it interacts with ATP7 on the plasma membrane to enable phosphatidylcholine flipping and midgut traversal required for mosquito transmission.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDC50C (PF3D7_1029400) is a P4-ATPase chaperone/flippase cofactor that partners with different P4-ATPase subunits in a stage- and species-dependent manner to support Plasmodium development and mosquito transmission [#0, #3]. In P. falciparum asexual blood stages, CDC50C is a direct binding partner of the putative phospholipid-transporting P4-ATPase ATP2, forming a CDC50C–ATP2 complex that is essential for intraerythrocytic development: conditional disruption of CDC50C arrests parasites at the trophozoite stage and impairs endocytosis of host hemoglobin and downstream hemozoin formation [#0, #1, #2]. In P. yoelii ookinetes, CDC50C instead co-localizes and physically interacts with the P4-ATPase ATP7 on the plasma membrane and acts as its flippase cofactor, with depletion phenocopying ATP7 deficiency and blocking mosquito midgut traversal and transmission [#3]. Beyond its role as a P4-ATPase partner in these two contexts, no additional catalytic or structural mechanism for CDC50C has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing a controllable way to deplete CDC50C was a prerequisite for probing its function, since the protein's essentiality could otherwise preclude genetic analysis.\",\n      \"evidence\": \"CRISPR/Cas9 AID tagging with auxin-induced degradation confirmed by Western blot/immunofluorescence across asexual, gametocyte, and ookinete stages in P. yoelii\",\n      \"pmids\": [\"33307135\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Primarily a tool-development study with limited mechanistic follow-up reported here\",\n        \"Does not itself assign a molecular function to CDC50C\",\n        \"No partner or substrate identified in this work\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether CDC50C acts as a dedicated cofactor for a specific P4-ATPase in transmission stages was resolved by showing it partners with ATP7 on the ookinete plasma membrane.\",\n      \"evidence\": \"Co-localization imaging, co-immunoprecipitation, and AID-mediated conditional depletion with mosquito-infection phenotyping in P. yoelii\",\n      \"pmids\": [\"34301597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical demonstration of lipid-flipping activity by the CDC50C–ATP7 complex not shown\",\n        \"Whether CDC50C partners with additional P4-ATPases in ookinetes not resolved\",\n        \"Species conservation of the ATP7 partnership to P. falciparum not tested\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium yoelii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The blood-stage function of CDC50C was defined by identifying ATP2 as its partner and linking the complex to trophozoite maturation, hemoglobin endocytosis, and hemozoin formation.\",\n      \"evidence\": \"Gene tagging, co-immunoprecipitation, and conditional gene disruption with developmental, hemoglobin-uptake, and hemozoin readouts in P. falciparum\",\n      \"pmids\": [\"35862778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct enzymatic/flippase activity of the CDC50C–ATP2 complex not demonstrated biochemically\",\n        \"Mechanistic link between phospholipid transport and hemoglobin endocytosis not resolved\",\n        \"Single-lab characterization\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether CDC50C directly confers or regulates phospholipid-flipping catalysis and how its partner choice (ATP2 vs ATP7) is determined across stages and species.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of CDC50C or its P4-ATPase complexes\",\n        \"No reconstituted biochemical assay of flippase activity\",\n        \"Rules governing partner specificity across life-cycle stages unresolved\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140326\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0045332\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0006897\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"CDC50C–ATP2 complex (P. falciparum)\",\n      \"CDC50C–ATP7 complex (P. yoelii)\"\n    ],\n    \"partners\": [\n      \"ATP2 (P4-ATPase, P. falciparum)\",\n      \"ATP7 (P4-ATPase, P. yoelii)\"\n    ],\n    \"other_free_text\": [\n      \"Essential for P. falciparum intraerythrocytic trophozoite maturation [#1]\",\n      \"Required for P. yoelii mosquito midgut traversal and transmission [#3]\",\n      \"Conditional depletion validated via auxin-inducible degron in P. yoelii [#4]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1029400","name":null,"product":"cell division control protein CDC50C","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0513400","name":null,"product":"LEM3/CDC50 family protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0614100","name":null,"product":"cell division control protein CDC50C, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"CDC50C","evaluation":null}