{"gene":"PF3D7_1138700","run_date":"2026-09-08T19:44:17","timeline":{"discoveries":[{"year":2023,"finding":"Disruption of KIC5 (via piggyBac transposon insertion near its transcription start site) in P. falciparum altered sensitivity to artemisinin and produced transcriptional changes associated with DNA stress response and altered mitochondrial metabolism during intraerythrocytic asexual development, functionally linking KIC5 dysregulation to the parasite's ability to respond to ART exposure at early ring stage.","method":"piggyBac transposon mutagenesis; transcriptomic profiling of KIC5 mutant; phenotype analysis during intraerythrocytic asexual development","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined cellular phenotype with transcriptomic data from loss-of-function mutant, single lab, single approach","pmids":["36624300"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"AlphaFold2 structural predictions revealed that KIC5 contains a clathrin adaptor α/β/γ-adaptin domain and an α-adaptin appendage C-terminal subdomain, showing structural similarity to AP complex subunit α, but lacking the canonical Adaptin_N domain, indicating KIC5 has some similarity to AP complex subunit α with profound differences from canonical adaptors.","method":"AlphaFold2 structural prediction with domain identification and comparison to PDB structures","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational structural prediction only, no experimental validation of domain function","pmids":["38039338"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"KIC5 truncation (KIC5-TGD) parasites showed reduced parasite and food vacuole size but no detectable difference in the bloated food vacuole endocytosis assay compared to 3D7 parasites, indicating KIC5 does not have an absolute role in host cell cytosol endocytosis in trophozoites, though a non-absolute effect cannot be excluded.","method":"Truncation of gene domain (TGD); bloated food vacuole assay for endocytosis; parasite size measurement","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional assay with defined cellular readout, single lab; negative endocytosis result with positive size phenotype","pmids":["38039338"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2024,"finding":"Testing 131 mutations across 10 K13 compartment proteins including KIC5 (via multi-mutant parasites with recodonized sequences introduced by SLI) showed that none of the KIC5 mutations tested conferred ART resistance in the ring-stage survival assay.","method":"Selection-linked integration (SLI) to introduce multiple KIC5 mutations; ring-stage survival assay (RSA) with dihydroartemisinin","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct genetic manipulation with defined functional readout (RSA), single lab; result is negative for ART resistance from KIC5 mutations","pmids":["38700363"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2024,"finding":"Attempts to simultaneously disrupt both KIC4 and KIC5, or combine their disruption with UBP1 R3138H, failed despite six attempts per combination, suggesting that the combined fitness cost of disrupting KIC5 together with KIC4 or UBP1 R3138H is prohibitive.","method":"Attempted genetic disruption by transfection (multiple failed attempts)","journal":"mBio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — negative/failed genetic manipulation, single lab, indirect inference about fitness cost","pmids":["38700363"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"KIC5 (PF3D7_1138700) is a P. falciparum K13 compartment protein that, when disrupted, reduces parasite and food vacuole size and alters the artemisinin stress-response transcriptome (including DNA stress response and mitochondrial metabolism genes) without detectably impairing trophozoite-stage hemoglobin endocytosis; AlphaFold2 predictions suggest it carries partial structural homology to AP complex subunit α (clathrin adaptor domains), but tested KIC5 point mutations do not confer artemisinin resistance, and the protein appears to contribute to parasite fitness rather than directly mediating ART susceptibility through endocytosis."},"narrative":{"mechanistic_narrative":"KIC5 (PF3D7_1138700) is a Plasmodium falciparum K13 compartment protein that contributes to intraerythrocytic parasite fitness and modulates the response to artemisinin (ART) stress rather than directly mediating ART susceptibility [PMID:36624300, PMID:38700363]. Disruption of KIC5 alters parasite sensitivity to artemisinin and remodels the asexual-stage transcriptome, including genes linked to the DNA stress response and mitochondrial metabolism, connecting KIC5 to how early ring-stage parasites cope with ART exposure [PMID:36624300]. Truncation of KIC5 reduces both parasite and food vacuole size but leaves trophozoite-stage host-cytosol endocytosis (measured by bloated food vacuole assay) intact, indicating KIC5 has no absolute role in hemoglobin endocytosis [PMID:38039338]. Consistent with a fitness rather than resistance role, none of the tested KIC5 point mutations confer ART resistance in the ring-stage survival assay [PMID:38700363], and combined disruption of KIC5 with KIC4 or with UBP1 R3138H could not be achieved, pointing to a prohibitive combined fitness cost [PMID:38700363]. Beyond these functional observations and an AlphaFold2 prediction of partial structural similarity to AP complex subunit α [PMID:38039338], no direct molecular activity or binding partners of KIC5 have been characterized in the available corpus.","teleology":[{"year":2023,"claim":"To ask whether KIC5 influences the parasite's handling of artemisinin, loss-of-function was linked to ART sensitivity and stress-response gene expression, establishing KIC5 as a modulator of the ART stress response.","evidence":"piggyBac transposon disruption with transcriptomic profiling during intraerythrocytic asexual development in P. falciparum","pmids":["36624300"],"confidence":"Medium","gaps":["Does not identify the molecular activity of KIC5 driving these transcriptional changes","Single lab, single approach; direct mechanism linking KIC5 to DNA stress and mitochondrial genes unresolved","No demonstration that transcriptional changes cause the altered ART sensitivity"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"To determine whether KIC5 acts through the K13-compartment endocytosis pathway, its truncation was tested for effects on food vacuole size and host-cytosol uptake, showing a size defect but no absolute endocytosis role.","evidence":"gene truncation (TGD) with bloated food vacuole endocytosis assay and parasite size measurement in P. falciparum 3D7","pmids":["38039338"],"confidence":"Medium","gaps":["Cannot exclude a non-absolute contribution to endocytosis","Mechanism connecting KIC5 to parasite and food vacuole size is unknown","No direct assessment of KIC5 protein localization or interactions"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2023,"claim":"To infer KIC5's molecular nature in the absence of biochemical data, AlphaFold2 was used to model its domains, revealing partial similarity to AP complex subunit α clathrin adaptor domains while lacking the canonical Adaptin_N domain.","evidence":"AlphaFold2 structural prediction with domain identification and comparison to PDB structures","pmids":["38039338"],"confidence":"Low","gaps":["Computational prediction only, with no experimental validation of adaptor function","Absence of the canonical Adaptin_N domain means the functional analogy is uncertain","No evidence KIC5 participates in a clathrin-adaptor or AP-like complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"To test whether KIC5 sequence variation drives artemisinin resistance, multiple recodonized KIC5 mutations were introduced and assayed, showing none confer resistance and reframing KIC5 as a fitness rather than resistance determinant.","evidence":"selection-linked integration of multi-mutant KIC5 with ring-stage survival assay against dihydroartemisinin in P. falciparum 3D7","pmids":["38700363"],"confidence":"Medium","gaps":["Negative result cannot exclude untested mutations or contexts affecting ART response","Does not define what fitness process KIC5 supports"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2024,"claim":"To probe genetic interactions, combined disruption of KIC5 with KIC4 or UBP1 R3138H was attempted and repeatedly failed, implying a prohibitive combined fitness cost.","evidence":"repeated attempted genetic disruption by transfection (six failed attempts per combination) in P. falciparum","pmids":["38700363"],"confidence":"Low","gaps":["Failed genetic manipulation gives only indirect inference of fitness cost, not direct measurement","No mechanistic explanation for the apparent synthetic lethality","Does not establish a physical or functional partnership between KIC5 and KIC4/UBP1"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The direct molecular activity, binding partners, and precise cellular role of KIC5 within the K13 compartment remain undefined.","evidence":"no discovery in the corpus establishes KIC5 substrates, interactors, or a validated biochemical function","pmids":[],"confidence":"Low","gaps":["No experimentally validated molecular activity for KIC5","No confirmed protein interaction partners or complex membership","Mechanism linking KIC5 to parasite/food vacuole size and ART stress response unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["KIC5 is a K13 compartment protein of P. falciparum whose disruption alters ART sensitivity and remodels DNA stress and mitochondrial metabolism transcripts [#0].","KIC5 truncation reduces parasite and food vacuole size without abolishing trophozoite host-cytosol endocytosis [#2].","AlphaFold2 predicts partial similarity to AP complex subunit α (clathrin adaptor domains) but with loss of the canonical Adaptin_N domain; no experimental validation [#1].","Tested KIC5 point mutations do not confer artemisinin resistance in RSA [#3].","Combined disruption of KIC5 with KIC4 or UBP1 R3138H repeatedly failed, implying a prohibitive combined fitness cost [#4]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"36624300","id":"PMC_36624300","title":"Protein KIC5 is a novel regulator of artemisinin stress response in the malaria parasite Plasmodium falciparum.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36624300","citation_count":12,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC5"],"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":["KIC5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41599764","id":"","title":"Targeting Infected Host Cell Heme Metabolism to Kill Malaria Parasites.","date":"2026","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41599764","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39639029","id":"","title":"Population genomics and transcriptomics of Plasmodium falciparum in Cambodia and Vietnam uncover key components of the artemisinin resistance genetic background.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39639029","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38413566","id":"","title":"Deaggregation of mutant Plasmodium yoelii de-ubiquitinase UBP1 alters MDR1 localization to confer multidrug resistance.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38413566","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC5"],"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":["KIC5"],"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":["KIC5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34102588","id":"","title":"Integration of population and functional genomics to understand mechanisms of artemisinin resistance in Plasmodium falciparum.","date":"2021","source":"International journal for parasitology. Drugs and drug resistance","url":"https://pubmed.ncbi.nlm.nih.gov/34102588","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"34606334","id":"","title":"Mutation in the Plasmodium falciparum BTB/POZ Domain of K13 Protein Confers Artemisinin Resistance.","date":"2021","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/34606334","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC5"],"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":["KIC5"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12765,"output_tokens":1405,"usd":0.029685,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6409,"output_tokens":2692,"usd":0.049673,"stage2_stop_reason":"end_turn"},"total_usd":0.079358,"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\": \"Disruption of KIC5 (via piggyBac transposon insertion near its transcription start site) in P. falciparum altered sensitivity to artemisinin and produced transcriptional changes associated with DNA stress response and altered mitochondrial metabolism during intraerythrocytic asexual development, functionally linking KIC5 dysregulation to the parasite's ability to respond to ART exposure at early ring stage.\",\n      \"method\": \"piggyBac transposon mutagenesis; transcriptomic profiling of KIC5 mutant; phenotype analysis during intraerythrocytic asexual development\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined cellular phenotype with transcriptomic data from loss-of-function mutant, single lab, single approach\",\n      \"pmids\": [\"36624300\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AlphaFold2 structural predictions revealed that KIC5 contains a clathrin adaptor α/β/γ-adaptin domain and an α-adaptin appendage C-terminal subdomain, showing structural similarity to AP complex subunit α, but lacking the canonical Adaptin_N domain, indicating KIC5 has some similarity to AP complex subunit α with profound differences from canonical adaptors.\",\n      \"method\": \"AlphaFold2 structural prediction with domain identification and comparison to PDB structures\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational structural prediction only, no experimental validation of domain function\",\n      \"pmids\": [\"38039338\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIC5 truncation (KIC5-TGD) parasites showed reduced parasite and food vacuole size but no detectable difference in the bloated food vacuole endocytosis assay compared to 3D7 parasites, indicating KIC5 does not have an absolute role in host cell cytosol endocytosis in trophozoites, though a non-absolute effect cannot be excluded.\",\n      \"method\": \"Truncation of gene domain (TGD); bloated food vacuole assay for endocytosis; parasite size measurement\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional assay with defined cellular readout, single lab; negative endocytosis result with positive size phenotype\",\n      \"pmids\": [\"38039338\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Testing 131 mutations across 10 K13 compartment proteins including KIC5 (via multi-mutant parasites with recodonized sequences introduced by SLI) showed that none of the KIC5 mutations tested conferred ART resistance in the ring-stage survival assay.\",\n      \"method\": \"Selection-linked integration (SLI) to introduce multiple KIC5 mutations; ring-stage survival assay (RSA) with dihydroartemisinin\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct genetic manipulation with defined functional readout (RSA), single lab; result is negative for ART resistance from KIC5 mutations\",\n      \"pmids\": [\"38700363\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Attempts to simultaneously disrupt both KIC4 and KIC5, or combine their disruption with UBP1 R3138H, failed despite six attempts per combination, suggesting that the combined fitness cost of disrupting KIC5 together with KIC4 or UBP1 R3138H is prohibitive.\",\n      \"method\": \"Attempted genetic disruption by transfection (multiple failed attempts)\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — negative/failed genetic manipulation, single lab, indirect inference about fitness cost\",\n      \"pmids\": [\"38700363\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"KIC5 (PF3D7_1138700) is a P. falciparum K13 compartment protein that, when disrupted, reduces parasite and food vacuole size and alters the artemisinin stress-response transcriptome (including DNA stress response and mitochondrial metabolism genes) without detectably impairing trophozoite-stage hemoglobin endocytosis; AlphaFold2 predictions suggest it carries partial structural homology to AP complex subunit α (clathrin adaptor domains), but tested KIC5 point mutations do not confer artemisinin resistance, and the protein appears to contribute to parasite fitness rather than directly mediating ART susceptibility through endocytosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIC5 (PF3D7_1138700) is a Plasmodium falciparum K13 compartment protein that contributes to intraerythrocytic parasite fitness and modulates the response to artemisinin (ART) stress rather than directly mediating ART susceptibility [#0, #3]. Disruption of KIC5 alters parasite sensitivity to artemisinin and remodels the asexual-stage transcriptome, including genes linked to the DNA stress response and mitochondrial metabolism, connecting KIC5 to how early ring-stage parasites cope with ART exposure [#0]. Truncation of KIC5 reduces both parasite and food vacuole size but leaves trophozoite-stage host-cytosol endocytosis (measured by bloated food vacuole assay) intact, indicating KIC5 has no absolute role in hemoglobin endocytosis [#2]. Consistent with a fitness rather than resistance role, none of the tested KIC5 point mutations confer ART resistance in the ring-stage survival assay [#3], and combined disruption of KIC5 with KIC4 or with UBP1 R3138H could not be achieved, pointing to a prohibitive combined fitness cost [#4]. Beyond these functional observations and an AlphaFold2 prediction of partial structural similarity to AP complex subunit \\u03b1 [#1], no direct molecular activity or binding partners of KIC5 have been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"To ask whether KIC5 influences the parasite's handling of artemisinin, loss-of-function was linked to ART sensitivity and stress-response gene expression, establishing KIC5 as a modulator of the ART stress response.\",\n      \"evidence\": \"piggyBac transposon disruption with transcriptomic profiling during intraerythrocytic asexual development in P. falciparum\",\n      \"pmids\": [\"36624300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not identify the molecular activity of KIC5 driving these transcriptional changes\",\n        \"Single lab, single approach; direct mechanism linking KIC5 to DNA stress and mitochondrial genes unresolved\",\n        \"No demonstration that transcriptional changes cause the altered ART sensitivity\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To determine whether KIC5 acts through the K13-compartment endocytosis pathway, its truncation was tested for effects on food vacuole size and host-cytosol uptake, showing a size defect but no absolute endocytosis role.\",\n      \"evidence\": \"gene truncation (TGD) with bloated food vacuole endocytosis assay and parasite size measurement in P. falciparum 3D7\",\n      \"pmids\": [\"38039338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cannot exclude a non-absolute contribution to endocytosis\",\n        \"Mechanism connecting KIC5 to parasite and food vacuole size is unknown\",\n        \"No direct assessment of KIC5 protein localization or interactions\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To infer KIC5's molecular nature in the absence of biochemical data, AlphaFold2 was used to model its domains, revealing partial similarity to AP complex subunit \\u03b1 clathrin adaptor domains while lacking the canonical Adaptin_N domain.\",\n      \"evidence\": \"AlphaFold2 structural prediction with domain identification and comparison to PDB structures\",\n      \"pmids\": [\"38039338\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Computational prediction only, with no experimental validation of adaptor function\",\n        \"Absence of the canonical Adaptin_N domain means the functional analogy is uncertain\",\n        \"No evidence KIC5 participates in a clathrin-adaptor or AP-like complex\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To test whether KIC5 sequence variation drives artemisinin resistance, multiple recodonized KIC5 mutations were introduced and assayed, showing none confer resistance and reframing KIC5 as a fitness rather than resistance determinant.\",\n      \"evidence\": \"selection-linked integration of multi-mutant KIC5 with ring-stage survival assay against dihydroartemisinin in P. falciparum 3D7\",\n      \"pmids\": [\"38700363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Negative result cannot exclude untested mutations or contexts affecting ART response\",\n        \"Does not define what fitness process KIC5 supports\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To probe genetic interactions, combined disruption of KIC5 with KIC4 or UBP1 R3138H was attempted and repeatedly failed, implying a prohibitive combined fitness cost.\",\n      \"evidence\": \"repeated attempted genetic disruption by transfection (six failed attempts per combination) in P. falciparum\",\n      \"pmids\": [\"38700363\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Failed genetic manipulation gives only indirect inference of fitness cost, not direct measurement\",\n        \"No mechanistic explanation for the apparent synthetic lethality\",\n        \"Does not establish a physical or functional partnership between KIC5 and KIC4/UBP1\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular activity, binding partners, and precise cellular role of KIC5 within the K13 compartment remain undefined.\",\n      \"evidence\": \"no discovery in the corpus establishes KIC5 substrates, interactors, or a validated biochemical function\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No experimentally validated molecular activity for KIC5\",\n        \"No confirmed protein interaction partners or complex membership\",\n        \"Mechanism linking KIC5 to parasite/food vacuole size and ART stress response unresolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"response to artemisinin/xenobiotic stress\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"KIC5 is a K13 compartment protein of P. falciparum whose disruption alters ART sensitivity and remodels DNA stress and mitochondrial metabolism transcripts [#0].\",\n      \"KIC5 truncation reduces parasite and food vacuole size without abolishing trophozoite host-cytosol endocytosis [#2].\",\n      \"AlphaFold2 predicts partial similarity to AP complex subunit \\u03b1 (clathrin adaptor domains) but with loss of the canonical Adaptin_N domain; no experimental validation [#1].\",\n      \"Tested KIC5 point mutations do not confer artemisinin resistance in RSA [#3].\",\n      \"Combined disruption of KIC5 with KIC4 or UBP1 R3138H repeatedly failed, implying a prohibitive combined fitness cost [#4].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1138700","name":null,"product":"protein KIC5","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0910000","name":null,"product":"protein KIC5, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0936900","name":null,"product":"protein KIC5, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"KIC5","evaluation":null}