{"gene":"PF3D7_1218300","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2013,"finding":"A non-synonymous substitution in the AP2-MU gene (encoding the μ-chain of the AP2 adaptor complex) in Plasmodium chabaudi is associated with an increased artemisinin resistance phenotype; homology modelling indicates that the mutated residue interacts with a cargo recognition sequence, suggesting involvement of endocytosis and membrane protein trafficking.","method":"Whole-genome re-sequencing (Illumina) of resistant mutant vs. progenitor parasite line; homology modelling of the mutated residue","journal":"Malaria journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational homology modelling only for the mechanistic claim; the resistance association is genetic but no direct biochemical or functional experiment on AP2-MU was performed","pmids":["23561245"],"is_preprint":false,"attribution":[{"species":"Plasmodium chabaudi","strain":""}]},{"year":2015,"finding":"Transgenic P. falciparum parasites constitutively expressing the AP2-MU 160Asn allele (vs. wild-type Ser160) showed significantly reduced sensitivity to dihydroartemisinin in a standard 48-h in vitro assay, and AP2-MU variants also modulated parasite sensitivity to quinine, directly demonstrating that PF3D7_1218300 modulates responses to multiple antimalarial drugs.","method":"Generation of transgenic P. falciparum parasites expressing codon-160 variants of AP2-MU (Ser vs. Asn); 48-h in vitro drug sensitivity assays","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean transgenic allelic-replacement with defined phenotypic readout, single lab, two drug conditions tested","pmids":["25691625"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Conditional knockout of AP2-MU in P. falciparum severely disrupted schizont organisation and maturation, causing mislocalization of key merozoite proteins, establishing that AP2-MU is essential for blood-stage replication.","method":"Conditional gene knockout; fluorescence microscopy; electron microscopy","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined morphological and protein-localization phenotype, multiple orthogonal microscopy methods in a single rigorous study","pmids":["32098816"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"finding":"Hemagglutinin-tagged AP2-MU co-immunoprecipitated other AP-2 subunits, the K10 kelch-domain protein, and PfEHD (an effector of endocytosis and lipid mobilization), identifying these as AP2-MU interaction partners; no interaction with clathrin was detected. Reverse immunoprecipitation with a clathrin nanobody retrieved other heterotetrameric AP-complexes but not AP-2 subunits, demonstrating that P. falciparum AP2-MU functions independently of clathrin.","method":"HA-tag immunoprecipitation followed by mass spectrometry; reverse immunoprecipitation with clathrin nanobody; fluorescence and electron microscopy","journal":"mBio","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-IP/nanobody IP with mass spectrometry identification, orthogonal microscopy, multiple controls in a single rigorous study","pmids":["32098816"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"In P. falciparum, AP2-MU (PF3D7_1218300) encodes the μ subunit of a clathrin-independent AP-2 adaptin complex that is essential for blood-stage schizont maturation and correct merozoite protein localisation; it physically interacts with other AP-2 subunits, the K10 kelch-domain protein, and PfEHD, and variants at residue 160 modulate parasite sensitivity to dihydroartemisinin and quinine."},"narrative":{"mechanistic_narrative":"AP2-MU (PF3D7_1218300) encodes the μ subunit of the AP-2 adaptin complex in Plasmodium falciparum and is essential for blood-stage replication, where conditional loss of the gene severely disrupts schizont organisation and maturation and causes mislocalization of key merozoite proteins [PMID:32098816]. AP2-MU physically associates with other AP-2 subunits, the K10 kelch-domain protein, and the endocytic/lipid-mobilization effector PfEHD, but functions independently of clathrin — no clathrin interaction was detected by reciprocal immunoprecipitation, distinguishing the parasite AP-2 complex from the canonical clathrin-dependent adaptor [PMID:32098816]. Consistent with a role in cargo recognition and membrane protein trafficking, allelic variants at residue 160 modulate parasite sensitivity to dihydroartemisinin and quinine [PMID:25691625, PMID:23561245]. Beyond these findings, the precise cargo repertoire and the trafficking step at which AP2-MU acts have not been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Before this work it was unknown whether the AP2 adaptor μ-chain contributed to antimalarial drug response; a resistance-associated coding substitution linked the gene to endocytosis and membrane protein trafficking.","evidence":"Whole-genome re-sequencing of a resistant Plasmodium chabaudi mutant vs. progenitor, with homology modelling of the mutated residue","pmids":["23561245"],"confidence":"Low","gaps":["Mechanistic claim rests on computational homology modelling only, with no direct biochemical assay on the μ-chain","Association derived from a rodent malaria model, not P. falciparum","No demonstration that the mutation alters cargo binding or trafficking"],"attribution":[{"species":"Plasmodium chabaudi","strain":""}]},{"year":2015,"claim":"To test whether the μ-chain variant is causally linked to drug response, defined codon-160 alleles were expressed in P. falciparum, establishing that the gene modulates sensitivity to multiple antimalarials.","evidence":"Transgenic P. falciparum expressing Ser160 vs. Asn160 AP2-MU variants assayed in 48-h in vitro dihydroartemisinin and quinine sensitivity assays","pmids":["25691625"],"confidence":"Medium","gaps":["Molecular mechanism linking residue 160 to drug sensitivity not defined","Single lab, two drug conditions","No link established between the variant and altered trafficking or cargo selection"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The essential cellular role of AP2-MU was unresolved; conditional knockout revealed it is required for schizont maturation and correct merozoite protein localisation, establishing an essential trafficking function in blood-stage parasites.","evidence":"Conditional gene knockout in P. falciparum with fluorescence and electron microscopy","pmids":["32098816"],"confidence":"High","gaps":["Specific cargo proteins whose mislocalization drives the phenotype not identified","Trafficking route (endocytic vs. secretory step) not resolved","Connection between the essential function and drug-sensitivity modulation not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2020,"claim":"The composition and clathrin-dependence of the parasite AP-2 complex were unknown; interaction mapping defined AP2-MU partners and showed the complex operates without clathrin, unlike its canonical counterpart.","evidence":"HA-tag immunoprecipitation with mass spectrometry, reciprocal clathrin-nanobody immunoprecipitation, and microscopy in P. falciparum","pmids":["32098816"],"confidence":"High","gaps":["Functional roles of K10 and PfEHD within the AP2-MU complex not dissected","Structural basis of clathrin independence not determined","Cargo-recognition specificity of the μ subunit not mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"It remains unknown which specific cargo proteins AP2-MU recognizes and at which membrane-trafficking step it acts, and how these functions mechanistically connect to modulation of antimalarial drug sensitivity.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No cargo repertoire defined for the μ subunit","Mechanism linking residue 160 variation to drug response unresolved","Trafficking step served by the clathrin-independent AP-2 complex unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["AP-2 adaptor complex (clathrin-independent, P. falciparum) [#3]"],"partners":["OTHER AP-2 SUBUNITS [#3]","K10 KELCH-DOMAIN PROTEIN [#3]","PFEHD [#3]"],"other_free_text":["Essential for blood-stage schizont organisation and maturation and for correct merozoite protein localisation [#2]","Codon-160 allelic variants (Ser/Asn) modulate parasite sensitivity to dihydroartemisinin and quinine [#1, #0]","P. falciparum AP-2 complex functions independently of clathrin; no clathrin interaction detected by reciprocal IP [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"23561245","id":"PMC_23561245","title":"Artemisinin resistance in rodent malaria--mutation in the AP2 adaptor μ-chain suggests involvement of endocytosis and membrane protein trafficking.","date":"2013","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/23561245","citation_count":51,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25691625","id":"PMC_25691625","title":"The Mu subunit of Plasmodium falciparum clathrin-associated adaptor protein 2 modulates in vitro parasite response to artemisinin and quinine.","date":"2015","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/25691625","citation_count":40,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AP2-MU","PfAP2-MU","PcAP2-MU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32098816","id":"PMC_32098816","title":"The Plasmodium falciparum Artemisinin Susceptibility-Associated AP-2 Adaptin μ Subunit is Clathrin Independent and Essential for Schizont Maturation.","date":"2020","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/32098816","citation_count":33,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["curated_ref"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31756512","id":"PMC_31756512","title":"Prevalence of mutations in Plasmodium falciparum genes associated with resistance to different antimalarial drugs in Nyando, Kisumu County in Kenya.","date":"2019","source":"Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31756512","citation_count":8,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfAP2-MU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42415199","id":"PMC_42415199","title":"Drug resistance gene polymorphisms of Plasmodium falciparum clinical isolates from Kinshasa, Democratic Republic of the Congo.","date":"2026","source":"Tropical medicine and health","url":"https://pubmed.ncbi.nlm.nih.gov/42415199","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["AP2-MU"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6144,"output_tokens":1222,"usd":0.018381,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6122,"output_tokens":2207,"usd":0.042893,"stage2_stop_reason":"end_turn"},"total_usd":0.061274,"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\": 2013,\n      \"finding\": \"A non-synonymous substitution in the AP2-MU gene (encoding the μ-chain of the AP2 adaptor complex) in Plasmodium chabaudi is associated with an increased artemisinin resistance phenotype; homology modelling indicates that the mutated residue interacts with a cargo recognition sequence, suggesting involvement of endocytosis and membrane protein trafficking.\",\n      \"method\": \"Whole-genome re-sequencing (Illumina) of resistant mutant vs. progenitor parasite line; homology modelling of the mutated residue\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational homology modelling only for the mechanistic claim; the resistance association is genetic but no direct biochemical or functional experiment on AP2-MU was performed\",\n      \"pmids\": [\"23561245\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium chabaudi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Transgenic P. falciparum parasites constitutively expressing the AP2-MU 160Asn allele (vs. wild-type Ser160) showed significantly reduced sensitivity to dihydroartemisinin in a standard 48-h in vitro assay, and AP2-MU variants also modulated parasite sensitivity to quinine, directly demonstrating that PF3D7_1218300 modulates responses to multiple antimalarial drugs.\",\n      \"method\": \"Generation of transgenic P. falciparum parasites expressing codon-160 variants of AP2-MU (Ser vs. Asn); 48-h in vitro drug sensitivity assays\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean transgenic allelic-replacement with defined phenotypic readout, single lab, two drug conditions tested\",\n      \"pmids\": [\"25691625\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional knockout of AP2-MU in P. falciparum severely disrupted schizont organisation and maturation, causing mislocalization of key merozoite proteins, establishing that AP2-MU is essential for blood-stage replication.\",\n      \"method\": \"Conditional gene knockout; fluorescence microscopy; electron microscopy\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined morphological and protein-localization phenotype, multiple orthogonal microscopy methods in a single rigorous study\",\n      \"pmids\": [\"32098816\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hemagglutinin-tagged AP2-MU co-immunoprecipitated other AP-2 subunits, the K10 kelch-domain protein, and PfEHD (an effector of endocytosis and lipid mobilization), identifying these as AP2-MU interaction partners; no interaction with clathrin was detected. Reverse immunoprecipitation with a clathrin nanobody retrieved other heterotetrameric AP-complexes but not AP-2 subunits, demonstrating that P. falciparum AP2-MU functions independently of clathrin.\",\n      \"method\": \"HA-tag immunoprecipitation followed by mass spectrometry; reverse immunoprecipitation with clathrin nanobody; fluorescence and electron microscopy\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-IP/nanobody IP with mass spectrometry identification, orthogonal microscopy, multiple controls in a single rigorous study\",\n      \"pmids\": [\"32098816\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"In P. falciparum, AP2-MU (PF3D7_1218300) encodes the μ subunit of a clathrin-independent AP-2 adaptin complex that is essential for blood-stage schizont maturation and correct merozoite protein localisation; it physically interacts with other AP-2 subunits, the K10 kelch-domain protein, and PfEHD, and variants at residue 160 modulate parasite sensitivity to dihydroartemisinin and quinine.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AP2-MU (PF3D7_1218300) encodes the μ subunit of the AP-2 adaptin complex in Plasmodium falciparum and is essential for blood-stage replication, where conditional loss of the gene severely disrupts schizont organisation and maturation and causes mislocalization of key merozoite proteins [#2]. AP2-MU physically associates with other AP-2 subunits, the K10 kelch-domain protein, and the endocytic/lipid-mobilization effector PfEHD, but functions independently of clathrin — no clathrin interaction was detected by reciprocal immunoprecipitation, distinguishing the parasite AP-2 complex from the canonical clathrin-dependent adaptor [#3]. Consistent with a role in cargo recognition and membrane protein trafficking, allelic variants at residue 160 modulate parasite sensitivity to dihydroartemisinin and quinine [#1, #0]. Beyond these findings, the precise cargo repertoire and the trafficking step at which AP2-MU acts have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Before this work it was unknown whether the AP2 adaptor μ-chain contributed to antimalarial drug response; a resistance-associated coding substitution linked the gene to endocytosis and membrane protein trafficking.\",\n      \"evidence\": \"Whole-genome re-sequencing of a resistant Plasmodium chabaudi mutant vs. progenitor, with homology modelling of the mutated residue\",\n      \"pmids\": [\"23561245\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic claim rests on computational homology modelling only, with no direct biochemical assay on the μ-chain\", \"Association derived from a rodent malaria model, not P. falciparum\", \"No demonstration that the mutation alters cargo binding or trafficking\"],\n      \"attribution\": [{\"species\": \"Plasmodium chabaudi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"To test whether the μ-chain variant is causally linked to drug response, defined codon-160 alleles were expressed in P. falciparum, establishing that the gene modulates sensitivity to multiple antimalarials.\",\n      \"evidence\": \"Transgenic P. falciparum expressing Ser160 vs. Asn160 AP2-MU variants assayed in 48-h in vitro dihydroartemisinin and quinine sensitivity assays\",\n      \"pmids\": [\"25691625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking residue 160 to drug sensitivity not defined\", \"Single lab, two drug conditions\", \"No link established between the variant and altered trafficking or cargo selection\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The essential cellular role of AP2-MU was unresolved; conditional knockout revealed it is required for schizont maturation and correct merozoite protein localisation, establishing an essential trafficking function in blood-stage parasites.\",\n      \"evidence\": \"Conditional gene knockout in P. falciparum with fluorescence and electron microscopy\",\n      \"pmids\": [\"32098816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific cargo proteins whose mislocalization drives the phenotype not identified\", \"Trafficking route (endocytic vs. secretory step) not resolved\", \"Connection between the essential function and drug-sensitivity modulation not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The composition and clathrin-dependence of the parasite AP-2 complex were unknown; interaction mapping defined AP2-MU partners and showed the complex operates without clathrin, unlike its canonical counterpart.\",\n      \"evidence\": \"HA-tag immunoprecipitation with mass spectrometry, reciprocal clathrin-nanobody immunoprecipitation, and microscopy in P. falciparum\",\n      \"pmids\": [\"32098816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional roles of K10 and PfEHD within the AP2-MU complex not dissected\", \"Structural basis of clathrin independence not determined\", \"Cargo-recognition specificity of the μ subunit not mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown which specific cargo proteins AP2-MU recognizes and at which membrane-trafficking step it acts, and how these functions mechanistically connect to modulation of antimalarial drug sensitivity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cargo repertoire defined for the μ subunit\", \"Mechanism linking residue 160 variation to drug response unresolved\", \"Trafficking step served by the clathrin-independent AP-2 complex unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0035615\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006897\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0015031\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"AP-2 adaptor complex (clathrin-independent, P. falciparum) [#3]\"],\n    \"partners\": [\"other AP-2 subunits [#3]\", \"K10 kelch-domain protein [#3]\", \"PfEHD [#3]\"],\n    \"other_free_text\": [\n      \"Essential for blood-stage schizont organisation and maturation and for correct merozoite protein localisation [#2]\",\n      \"Codon-160 allelic variants (Ser/Asn) modulate parasite sensitivity to dihydroartemisinin and quinine [#1, #0]\",\n      \"P. falciparum AP-2 complex functions independently of clathrin; no clathrin interaction detected by reciprocal IP [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1218300","name":null,"product":"AP-2 complex subunit mu","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1433900","name":null,"product":"AP-2 complex subunit mu, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1437900","name":null,"product":"AP-2 complex subunit mu, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"AP2-MU","evaluation":null}