{"gene":"PF3D7_1133300","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2022,"finding":"CDC50B (PF3D7_1133300) is expressed in asexual blood stages of P. falciparum and is a direct binding partner of guanylyl cyclase alpha (GCα), as demonstrated by gene tagging and conditional gene disruption experiments. CDC50B modulates the rate of merozoite egress by interacting with GCα for optimal cGMP synthesis, but is not essential for intraerythrocytic parasite maturation.","method":"Gene tagging, conditional gene disruption, co-immunoprecipitation","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding partner identification by Co-IP combined with conditional disruption showing defined egress phenotype, multiple orthogonal methods in a single rigorous study","pmids":["35862778"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2021,"finding":"In P. chabaudi, the CDC50B orthologue (PcCdc50B) associates with PcATP2 (P4-ATPase), and the purified PcATP2/PcCdc50B complex displays ATPase activity stimulated by phosphatidylserine or phosphatidylethanolamine, with further upregulation by phosphatidylinositol 4-phosphate. This constitutes the first biochemical demonstration that a Plasmodium CDC50B-containing complex functions as a lipid flippase.","method":"Recombinant protein expression, co-purification, in vitro ATPase activity assay","journal":"Emerging microbes & infections","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity with purified complex, single lab but multiple biochemical readouts","pmids":["33372863"],"is_preprint":false,"attribution":[{"species":"Plasmodium chabaudi","strain":""}]},{"year":2023,"finding":"CDC50B (PF3D7_1133300) was detected as a binding partner of GCα by affinity purification (cross-linking co-immunoprecipitation) from both P. berghei gametocytes and schizonts, suggesting it participates in a conserved GCα membrane signaling platform across parasite life cycle stages. Notably, CDC50B was not recovered in UGO immunoprecipitates, placing it in a distinct sub-complex of the platform.","method":"Cross-linking affinity purification / mass spectrometry (co-IP-MS) from P. berghei gametocytes and schizonts","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal affinity purification MS from two parasite stages in a single study, replicating the P. falciparum interaction finding from PMID:35862778","pmids":["37327340"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]}],"current_model":"CDC50B (PF3D7_1133300) is a chaperone/beta-subunit expressed in Plasmodium asexual blood stages and gametocytes that binds the N-terminal P4-ATPase domain of guanylyl cyclase alpha (GCα), thereby modulating cGMP synthesis and the efficiency of merozoite egress; its P. chabaudi orthologue reconstituted in vitro with PcATP2 displays phosphatidylserine/phosphatidylethanolamine-stimulated ATPase activity, indicating a lipid-flippase cofactor role, though within P. falciparum blood stages CDC50B is not essential for parasite maturation."},"narrative":{"mechanistic_narrative":"CDC50B (PF3D7_1133300) is a P4-ATPase beta-subunit/chaperone that functions within the guanylyl cyclase alpha (GCα) membrane signaling platform of Plasmodium blood and sexual stages [PMID:35862778, PMID:37327340]. In P. falciparum asexual blood stages, CDC50B is expressed and binds GCα directly, and this interaction supports optimal cGMP synthesis to set the rate of merozoite egress, although CDC50B is dispensable for intraerythrocytic maturation [PMID:35862778]. This association with GCα is conserved across life-cycle stages in P. berghei, where CDC50B is recovered with GCα from both gametocytes and schizonts but is excluded from UGO-containing immunoprecipitates, placing it in a distinct sub-complex of the platform [PMID:37327340]. Consistent with a lipid-flippase cofactor role, the P. chabaudi orthologue co-purifies with the P4-ATPase PcATP2 as a complex whose ATPase activity is stimulated by phosphatidylserine or phosphatidylethanolamine and further enhanced by phosphatidylinositol 4-phosphate [PMID:33372863]. Beyond these findings, the structural basis of CDC50B–partner recognition and its precise contribution to cGMP signaling remain uncharacterized in the available corpus.","teleology":[{"year":2021,"claim":"Whether a Plasmodium CDC50B-containing complex possesses lipid-transport enzymatic activity was unknown; reconstituting the orthologue with a P4-ATPase established it as a functional lipid-flippase cofactor.","evidence":"recombinant expression, co-purification, and in vitro ATPase assays of the PcATP2/PcCdc50B complex in P. chabaudi","pmids":["33372863"],"confidence":"High","gaps":["Direct lipid translocation (flipping) was inferred from ATPase stimulation rather than measured directly","Whether the P. falciparum CDC50B pairs with the same or a different P4-ATPase in vivo is not established","No structural model of the CDC50B/P4-ATPase interface"],"attribution":[{"species":"Plasmodium chabaudi","strain":""}]},{"year":2022,"claim":"The in vivo binding partner and blood-stage role of CDC50B were undefined; tagging, conditional disruption, and Co-IP identified GCα as a direct partner and linked CDC50B to the timing of merozoite egress via cGMP synthesis.","evidence":"gene tagging, conditional gene disruption, and co-immunoprecipitation in P. falciparum asexual blood stages","pmids":["35862778"],"confidence":"High","gaps":["How CDC50B binding to GCα mechanistically enhances cGMP output is not defined","CDC50B is not essential, leaving its non-redundant contribution unclear","Whether its flippase activity is functionally coupled to GCα regulation is not tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Whether the CDC50B–GCα association extends beyond asexual stages and how it is organized within the larger signaling platform were open; affinity purification across stages showed conservation and defined CDC50B as part of a sub-complex distinct from UGO.","evidence":"cross-linking affinity purification/mass spectrometry from P. berghei gametocytes and schizonts","pmids":["37327340"],"confidence":"Medium","gaps":["The functional consequence of CDC50B exclusion from the UGO sub-complex is unknown","Stoichiometry and architecture of the GCα platform are not resolved","No functional (loss-of-function) test of CDC50B was performed in P. berghei"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"It remains unknown how CDC50B's lipid-flippase cofactor activity is mechanistically integrated with its role in the GCα platform to control cGMP synthesis and egress timing.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CDC50B or its complexes","Direct link between flippase activity and cGMP regulation untested","Membrane lipid environment required for GCα activation not defined"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["GCα membrane signaling platform (P. falciparum, P. berghei)","PcATP2/PcCdc50B P4-ATPase flippase complex (P. chabaudi)"],"partners":["GUANYLYL CYCLASE ALPHA (GCΑ)","PCATP2 (P4-ATPASE, P. CHABAUDI ORTHOLOGUE)"],"other_free_text":["Expressed in P. falciparum asexual blood stages and P. berghei gametocytes and schizonts","Non-essential for P. falciparum intraerythrocytic maturation; modulates merozoite egress rate","Excluded from the UGO sub-complex, indicating membership in a distinct sub-complex of the GCα platform","Complex ATPase activity stimulated by phosphatidylserine/phosphatidylethanolamine and further by PI4P"]}},"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":["CDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33372863","id":"PMC_33372863","title":"ATP2, The essential P4-ATPase of malaria parasites, catalyzes lipid-stimulated ATP hydrolysis in complex with a Cdc50 β-subunit.","date":"2021","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/33372863","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PcCDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41144577","id":"","title":"PfATP2 is a flippase on the Plasmodium falciparum surface that is important for growth and influences parasite sensitivity to antiplasmodial compounds.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/41144577","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40823845","id":"","title":"Plasmodium falciparum PP1 phosphatase is a key regulator of malaria parasite transmission.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/40823845","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36820809","id":"","title":"The enemy within: lipid asymmetry in intracellular parasite-host interactions.","date":"2023","source":"Emerging topics in life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36820809","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39808636","id":"","title":"The malaria parasite PP1 phosphatase controls the initiation of the egress pathway of asexual blood-stages by regulating the rounding-up of the vacuole.","date":"2025","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/39808636","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37327340","id":"","title":"A Plasmodium membrane receptor platform integrates cues for egress and invasion in blood forms and activation of transmission stages.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37327340","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34301597","id":"","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":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["CDC50B"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11093,"output_tokens":1033,"usd":0.024387,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5816,"output_tokens":2208,"usd":0.04214,"stage2_stop_reason":"end_turn"},"total_usd":0.066527,"stage1_batch_id":"msgbatch_01SRp5hyRc82zNjddxyCCXGk","stage2_batch_id":"msgbatch_01K3BTmBazRo3pRrMvyaPMTY","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"CDC50B (PF3D7_1133300) is expressed in asexual blood stages of P. falciparum and is a direct binding partner of guanylyl cyclase alpha (GCα), as demonstrated by gene tagging and conditional gene disruption experiments. CDC50B modulates the rate of merozoite egress by interacting with GCα for optimal cGMP synthesis, but is not essential for intraerythrocytic parasite maturation.\",\n      \"method\": \"Gene tagging, conditional gene disruption, co-immunoprecipitation\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding partner identification by Co-IP combined with conditional disruption showing defined egress phenotype, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"35862778\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In P. chabaudi, the CDC50B orthologue (PcCdc50B) associates with PcATP2 (P4-ATPase), and the purified PcATP2/PcCdc50B complex displays ATPase activity stimulated by phosphatidylserine or phosphatidylethanolamine, with further upregulation by phosphatidylinositol 4-phosphate. This constitutes the first biochemical demonstration that a Plasmodium CDC50B-containing complex functions as a lipid flippase.\",\n      \"method\": \"Recombinant protein expression, co-purification, in vitro ATPase activity assay\",\n      \"journal\": \"Emerging microbes & infections\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of enzymatic activity with purified complex, single lab but multiple biochemical readouts\",\n      \"pmids\": [\"33372863\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium chabaudi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDC50B (PF3D7_1133300) was detected as a binding partner of GCα by affinity purification (cross-linking co-immunoprecipitation) from both P. berghei gametocytes and schizonts, suggesting it participates in a conserved GCα membrane signaling platform across parasite life cycle stages. Notably, CDC50B was not recovered in UGO immunoprecipitates, placing it in a distinct sub-complex of the platform.\",\n      \"method\": \"Cross-linking affinity purification / mass spectrometry (co-IP-MS) from P. berghei gametocytes and schizonts\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal affinity purification MS from two parasite stages in a single study, replicating the P. falciparum interaction finding from PMID:35862778\",\n      \"pmids\": [\"37327340\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"CDC50B (PF3D7_1133300) is a chaperone/beta-subunit expressed in Plasmodium asexual blood stages and gametocytes that binds the N-terminal P4-ATPase domain of guanylyl cyclase alpha (GCα), thereby modulating cGMP synthesis and the efficiency of merozoite egress; its P. chabaudi orthologue reconstituted in vitro with PcATP2 displays phosphatidylserine/phosphatidylethanolamine-stimulated ATPase activity, indicating a lipid-flippase cofactor role, though within P. falciparum blood stages CDC50B is not essential for parasite maturation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDC50B (PF3D7_1133300) is a P4-ATPase beta-subunit/chaperone that functions within the guanylyl cyclase alpha (GCα) membrane signaling platform of Plasmodium blood and sexual stages [#0, #2]. In P. falciparum asexual blood stages, CDC50B is expressed and binds GCα directly, and this interaction supports optimal cGMP synthesis to set the rate of merozoite egress, although CDC50B is dispensable for intraerythrocytic maturation [#0]. This association with GCα is conserved across life-cycle stages in P. berghei, where CDC50B is recovered with GCα from both gametocytes and schizonts but is excluded from UGO-containing immunoprecipitates, placing it in a distinct sub-complex of the platform [#2]. Consistent with a lipid-flippase cofactor role, the P. chabaudi orthologue co-purifies with the P4-ATPase PcATP2 as a complex whose ATPase activity is stimulated by phosphatidylserine or phosphatidylethanolamine and further enhanced by phosphatidylinositol 4-phosphate [#1]. Beyond these findings, the structural basis of CDC50B–partner recognition and its precise contribution to cGMP signaling remain uncharacterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether a Plasmodium CDC50B-containing complex possesses lipid-transport enzymatic activity was unknown; reconstituting the orthologue with a P4-ATPase established it as a functional lipid-flippase cofactor.\",\n      \"evidence\": \"recombinant expression, co-purification, and in vitro ATPase assays of the PcATP2/PcCdc50B complex in P. chabaudi\",\n      \"pmids\": [\"33372863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct lipid translocation (flipping) was inferred from ATPase stimulation rather than measured directly\",\n        \"Whether the P. falciparum CDC50B pairs with the same or a different P4-ATPase in vivo is not established\",\n        \"No structural model of the CDC50B/P4-ATPase interface\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium chabaudi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The in vivo binding partner and blood-stage role of CDC50B were undefined; tagging, conditional disruption, and Co-IP identified GCα as a direct partner and linked CDC50B to the timing of merozoite egress via cGMP synthesis.\",\n      \"evidence\": \"gene tagging, conditional gene disruption, and co-immunoprecipitation in P. falciparum asexual blood stages\",\n      \"pmids\": [\"35862778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How CDC50B binding to GCα mechanistically enhances cGMP output is not defined\",\n        \"CDC50B is not essential, leaving its non-redundant contribution unclear\",\n        \"Whether its flippase activity is functionally coupled to GCα regulation is not tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether the CDC50B–GCα association extends beyond asexual stages and how it is organized within the larger signaling platform were open; affinity purification across stages showed conservation and defined CDC50B as part of a sub-complex distinct from UGO.\",\n      \"evidence\": \"cross-linking affinity purification/mass spectrometry from P. berghei gametocytes and schizonts\",\n      \"pmids\": [\"37327340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The functional consequence of CDC50B exclusion from the UGO sub-complex is unknown\",\n        \"Stoichiometry and architecture of the GCα platform are not resolved\",\n        \"No functional (loss-of-function) test of CDC50B was performed in P. berghei\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how CDC50B's lipid-flippase cofactor activity is mechanistically integrated with its role in the GCα platform to control cGMP synthesis and egress timing.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structure of CDC50B or its complexes\",\n        \"Direct link between flippase activity and cGMP regulation untested\",\n        \"Membrane lipid environment required for GCα activation not defined\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140326\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0016887\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006182\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0035891\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"GCα membrane signaling platform (P. falciparum, P. berghei)\",\n      \"PcATP2/PcCdc50B P4-ATPase flippase complex (P. chabaudi)\"\n    ],\n    \"partners\": [\n      \"Guanylyl cyclase alpha (GCα)\",\n      \"PcATP2 (P4-ATPase, P. chabaudi orthologue)\"\n    ],\n    \"other_free_text\": [\n      \"Expressed in P. falciparum asexual blood stages and P. berghei gametocytes and schizonts\",\n      \"Non-essential for P. falciparum intraerythrocytic maturation; modulates merozoite egress rate\",\n      \"Excluded from the UGO sub-complex, indicating membership in a distinct sub-complex of the GCα platform\",\n      \"Complex ATPase activity stimulated by phosphatidylserine/phosphatidylethanolamine and further by PI4P\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1133300","name":null,"product":"cell division control protein CDC50B","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0915100","name":null,"product":"LEM3/CDC50 family protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0931400","name":null,"product":"cell division control protein CDC50B, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"CDC50B","evaluation":null}