{"gene":"PF3D7_1442400","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2023,"finding":"KIC9 (PF3D7_1442400) co-localizes with K13 at the K13 compartment in P. falciparum asexual blood stages, but unlike endocytosis-linked compartment members, it lacks detectable vesicle trafficking or endocytosis domains by AlphaFold2 structural comparison, and no role in ART resistance (by ring-stage survival assay) or host cell cytosol endocytosis was detected for KIC9.","method":"AlphaFold2 structural prediction, ring-stage survival assay (RSA), K13 compartment co-localization analysis","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RSA functional assay and structural analysis in single study; negative finding for endocytosis/ART resistance role is clearly established, co-localization at K13 compartment supported by prior BioID work referenced in paper","pmids":["38039338"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Introduction of multiple non-synonymous mutations in KIC9 (PF3D7_1442400) into P. falciparum 3D7 parasites using selection-linked integration did not confer reduced susceptibility to artemisinin as measured by ring-stage survival assay with dihydroartemisinin.","method":"Selection-linked integration (SLI) to generate multi-mutant parasites, ring-stage survival assay (RSA) with dihydroartemisinin","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic manipulation with functional assay in a single study; negative result clearly established","pmids":["38700363"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2021,"finding":"Knock-sideways mislocalization of KIC9 (PF3D7_1442400) rendered P. falciparum parasites resistant to artemisinin, implicating KIC9 in endocytosis of host cell hemoglobin at the K13 compartment.","method":"Knock-sideways system (conditional mislocalization), ring-stage survival assay","journal":"International journal for parasitology. Drugs and drug resistance","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — knock-sideways functional result attributed to a cited prior study (Birnbaum et al., 2020) described secondhand in a review; single method, single lab","pmids":["34090067"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"KIC9 (PF3D7_1442400) is a member of the K13 compartment in P. falciparum asexual blood stages; conditional mislocalization (knock-sideways) confers artemisinin resistance consistent with a role in host cell cytosol endocytosis, yet KIC9 lacks detectable vesicle trafficking domains by structural analysis, and direct introduction of multiple KIC9 mutations did not itself confer artemisinin resistance, leaving its precise molecular function within the K13 compartment undefined."},"narrative":{"mechanistic_narrative":"KIC9 (PF3D7_1442400) is a member of the K13 compartment in Plasmodium falciparum asexual blood stages, where it co-localizes with K13 [PMID:38039338]. Its role in the compartment is functionally ambiguous: conditional mislocalization of KIC9 by knock-sideways rendered parasites resistant to artemisinin, linking it to host cell hemoglobin endocytosis at the K13 compartment [PMID:34090067], yet AlphaFold2 structural analysis found no detectable vesicle trafficking or endocytosis domains, and no endocytosis or artemisinin-resistance role was detected for KIC9 in that same study [PMID:38039338]. Consistent with this, direct introduction of multiple non-synonymous KIC9 mutations into 3D7 parasites did not confer reduced artemisinin susceptibility by ring-stage survival assay [PMID:38700363]. Beyond its membership in the K13 compartment, the precise molecular function of KIC9 has not been characterized in the available corpus.","teleology":[{"year":2021,"claim":"To ask whether K13 compartment members beyond K13 itself contribute to artemisinin resistance, conditional mislocalization tested whether removing KIC9 from the compartment altered drug susceptibility.","evidence":"knock-sideways conditional mislocalization with ring-stage survival assay in P. falciparum","pmids":["34090067"],"confidence":"Medium","gaps":["result described secondhand in a review, single method and lab","does not define KIC9's direct molecular activity in endocytosis","does not establish physical partners of KIC9 within the compartment"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"To determine whether KIC9 is mechanistically a trafficking/endocytosis component, structural prediction and functional assays tested for endocytosis domains and a resistance phenotype independent of mislocalization.","evidence":"AlphaFold2 structural comparison, ring-stage survival assay, and K13 compartment co-localization in P. falciparum","pmids":["38039338"],"confidence":"Medium","gaps":["absence of predicted domains does not exclude an indirect or scaffolding role","co-localization does not identify direct binding partners","negative endocytosis result may reflect assay sensitivity"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"To test whether KIC9 sequence variation itself drives artemisinin resistance, defined mutations were introduced genetically and drug susceptibility measured.","evidence":"selection-linked integration to generate multi-mutant parasites, ring-stage survival assay with dihydroartemisinin in P. falciparum 3D7","pmids":["38700363"],"confidence":"Medium","gaps":["does not exclude a KIC9 loss-of-function contribution to resistance","specific mutations tested may not span functionally relevant residues","does not resolve why mislocalization but not mutation alters susceptibility"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":null,"claim":"The precise molecular function of KIC9 within the K13 compartment, and how its mislocalization confers resistance despite the absence of trafficking domains, remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no direct biochemical activity assigned to KIC9","no validated interaction partners identified for KIC9 itself","mechanism reconciling mislocalization phenotype with lack of domains and lack of mutation effect is unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["K13 compartment"],"partners":["K13 (CO-LOCALIZATION)"],"other_free_text":["Knock-sideways mislocalization of KIC9 confers artemisinin resistance [#2], but AlphaFold2 found no vesicle trafficking or endocytosis domains and no resistance/endocytosis role in a separate study [#0], and defined KIC9 mutations did not confer resistance [#1].","Corpus establishes KIC9 as a K13 compartment member; its independent molecular function is undefined."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"42115185","id":"PMC_42115185","title":"Global-scale population genetic analysis of Plasmodium falciparum identifies region-specific patterns of malaria parasite adaptation.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42115185","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfKIC9"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38700363","id":"","title":"Impact of different mutations on Kelch13 protein levels, ART resistance, and fitness cost in Plasmodium falciparum parasites.","date":"2024","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/38700363","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC9"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38039338","id":"","title":"The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites.","date":"2023","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/38039338","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC9"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34090067","id":"","title":"Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.","date":"2021","source":"International journal for parasitology. Drugs and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/34090067","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC9"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6662,"output_tokens":934,"usd":0.016998,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5648,"output_tokens":1848,"usd":0.03722,"stage2_stop_reason":"end_turn"},"total_usd":0.054218,"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\": 2023,\n      \"finding\": \"KIC9 (PF3D7_1442400) co-localizes with K13 at the K13 compartment in P. falciparum asexual blood stages, but unlike endocytosis-linked compartment members, it lacks detectable vesicle trafficking or endocytosis domains by AlphaFold2 structural comparison, and no role in ART resistance (by ring-stage survival assay) or host cell cytosol endocytosis was detected for KIC9.\",\n      \"method\": \"AlphaFold2 structural prediction, ring-stage survival assay (RSA), K13 compartment co-localization analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RSA functional assay and structural analysis in single study; negative finding for endocytosis/ART resistance role is clearly established, co-localization at K13 compartment supported by prior BioID work referenced in paper\",\n      \"pmids\": [\"38039338\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Introduction of multiple non-synonymous mutations in KIC9 (PF3D7_1442400) into P. falciparum 3D7 parasites using selection-linked integration did not confer reduced susceptibility to artemisinin as measured by ring-stage survival assay with dihydroartemisinin.\",\n      \"method\": \"Selection-linked integration (SLI) to generate multi-mutant parasites, ring-stage survival assay (RSA) with dihydroartemisinin\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic manipulation with functional assay in a single study; negative result clearly established\",\n      \"pmids\": [\"38700363\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Knock-sideways mislocalization of KIC9 (PF3D7_1442400) rendered P. falciparum parasites resistant to artemisinin, implicating KIC9 in endocytosis of host cell hemoglobin at the K13 compartment.\",\n      \"method\": \"Knock-sideways system (conditional mislocalization), ring-stage survival assay\",\n      \"journal\": \"International journal for parasitology. Drugs and drug resistance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — knock-sideways functional result attributed to a cited prior study (Birnbaum et al., 2020) described secondhand in a review; single method, single lab\",\n      \"pmids\": [\"34090067\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"KIC9 (PF3D7_1442400) is a member of the K13 compartment in P. falciparum asexual blood stages; conditional mislocalization (knock-sideways) confers artemisinin resistance consistent with a role in host cell cytosol endocytosis, yet KIC9 lacks detectable vesicle trafficking domains by structural analysis, and direct introduction of multiple KIC9 mutations did not itself confer artemisinin resistance, leaving its precise molecular function within the K13 compartment undefined.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KIC9 (PF3D7_1442400) is a member of the K13 compartment in Plasmodium falciparum asexual blood stages, where it co-localizes with K13 [#0]. Its role in the compartment is functionally ambiguous: conditional mislocalization of KIC9 by knock-sideways rendered parasites resistant to artemisinin, linking it to host cell hemoglobin endocytosis at the K13 compartment [#2], yet AlphaFold2 structural analysis found no detectable vesicle trafficking or endocytosis domains, and no endocytosis or artemisinin-resistance role was detected for KIC9 in that same study [#0]. Consistent with this, direct introduction of multiple non-synonymous KIC9 mutations into 3D7 parasites did not confer reduced artemisinin susceptibility by ring-stage survival assay [#1]. Beyond its membership in the K13 compartment, the precise molecular function of KIC9 has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"To ask whether K13 compartment members beyond K13 itself contribute to artemisinin resistance, conditional mislocalization tested whether removing KIC9 from the compartment altered drug susceptibility.\",\n      \"evidence\": \"knock-sideways conditional mislocalization with ring-stage survival assay in P. falciparum\",\n      \"pmids\": [\n        \"34090067\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"result described secondhand in a review, single method and lab\",\n        \"does not define KIC9's direct molecular activity in endocytosis\",\n        \"does not establish physical partners of KIC9 within the compartment\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To determine whether KIC9 is mechanistically a trafficking/endocytosis component, structural prediction and functional assays tested for endocytosis domains and a resistance phenotype independent of mislocalization.\",\n      \"evidence\": \"AlphaFold2 structural comparison, ring-stage survival assay, and K13 compartment co-localization in P. falciparum\",\n      \"pmids\": [\n        \"38039338\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"absence of predicted domains does not exclude an indirect or scaffolding role\",\n        \"co-localization does not identify direct binding partners\",\n        \"negative endocytosis result may reflect assay sensitivity\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To test whether KIC9 sequence variation itself drives artemisinin resistance, defined mutations were introduced genetically and drug susceptibility measured.\",\n      \"evidence\": \"selection-linked integration to generate multi-mutant parasites, ring-stage survival assay with dihydroartemisinin in P. falciparum 3D7\",\n      \"pmids\": [\n        \"38700363\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"does not exclude a KIC9 loss-of-function contribution to resistance\",\n        \"specific mutations tested may not span functionally relevant residues\",\n        \"does not resolve why mislocalization but not mutation alters susceptibility\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"3D7\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise molecular function of KIC9 within the K13 compartment, and how its mislocalization confers resistance despite the absence of trafficking domains, remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"no direct biochemical activity assigned to KIC9\",\n        \"no validated interaction partners identified for KIC9 itself\",\n        \"mechanism reconciling mislocalization phenotype with lack of domains and lack of mutation effect is unresolved\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\n        \"term_id\": \"K13 compartment\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"host cell hemoglobin endocytosis (artemisinin resistance)\",\n        \"supporting_discovery_ids\": [\n          2\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"K13 compartment\"\n    ],\n    \"partners\": [\n      \"K13 (co-localization)\"\n    ],\n    \"other_free_text\": [\n      \"Knock-sideways mislocalization of KIC9 confers artemisinin resistance [#2], but AlphaFold2 found no vesicle trafficking or endocytosis domains and no resistance/endocytosis role in a separate study [#0], and defined KIC9 mutations did not confer resistance [#1].\",\n      \"Corpus establishes KIC9 as a K13 compartment member; its independent molecular function is undefined.\"\n    ]\n  }\n}\n```","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1442400","name":null,"product":"protein KIC9","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1306300","name":null,"product":"protein KIC9, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1239900","name":null,"product":"protein KIC9, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"KIC9","evaluation":null}