{"gene":"PF3D7_1246300","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2023,"finding":"AlphaFold2 structural predictions revealed that KIC4 contains an unusual hybrid domain architecture: an N-terminal VHS domain, followed by a GAT domain, a clathrin adaptor α/β/γ adaptin appendage domain (typical of GGA vesicle adaptors), and an additional C-terminal β-adaptin appendage C-terminal subdomain not found in GGAs — a domain combination not previously observed in any other protein, suggesting KIC4 is a hybrid between GGA-type and AP complex β-subunit adaptors.","method":"AlphaFold2 structural prediction with domain comparison to PDB structures (RMSD-based alignment); domain annotation via InterPro","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational structural prediction only, no experimental validation of domain function or binding partners in vitro","pmids":["38039338"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"KIC4 is a member of the K13 compartment and belongs to the group of K13 compartment proteins that contain vesicle trafficking domains; however, the paper does not report a specific functional assay establishing whether KIC4 influences endocytosis or ART susceptibility.","method":"Localization by co-localisation with K13 (prior BioID data referenced); domain classification by AlphaFold2 prediction","journal":"PLoS pathogens","confidence":"Low","confidence_rationale":"Tier 4 / Weak — domain classification is computational; no direct experimental functional assay for KIC4 reported in this abstract","pmids":["38039338"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"KIC4 gene expression is down-regulated under low glucose stress conditions in P. falciparum, and PfGCN5 occupancy at the KIC4 promoter (5′ UTR) is significantly enriched under stress conditions in wild-type parasites but not in PfGCN5 knockdown parasites, indicating that PfGCN5 regulates KIC4 transcription under stress.","method":"RNA-seq transcriptomics under stress conditions; chromatin-immunoprecipitation quantitative PCR (ChIP-qPCR) at the KIC4 5′ UTR in wild-type vs. TetR-DOZI conditional PfGCN5 knockdown parasites","journal":"Antimicrobial agents and chemotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (RNA-seq and ChIP-qPCR) in a single lab; direct promoter occupancy evidence supports transcriptional regulation, but functional consequence of KIC4 down-regulation itself was not tested","pmids":["37702516"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"finding":"Introduction of multiple non-synonymous mutations in KIC4 (as part of a multi-mutant construct tested by ring-stage survival assay) did not confer ART resistance in P. falciparum 3D7 parasites, indicating that the tested KIC4 mutations are not sufficient to reduce artemisinin susceptibility.","method":"Selection-linked integration to introduce multi-mutant recodonized KIC4 sequence into 3D7 parasites; ring-stage survival assay (RSA) with dihydroartemisinin","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic approach with RSA functional readout, but this is a negative result and a single lab study","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) repeatedly failed across six independent attempts each, suggesting that combined loss of KIC4 and KIC5 is not tolerated, implying each is individually dispensable but together essential or synthetically lethal.","method":"Selection-linked integration-based gene disruption attempts (six independent attempts per combination) in P. falciparum","journal":"mBio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — inference from failed genetic experiments (negative result interpreted as synthetic lethality); no direct rescue or epistasis confirmation","pmids":["38700363"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]}],"current_model":"KIC4 (PF3D7_1246300) is a P. falciparum K13 compartment protein with a unique hybrid domain architecture (VHS–GAT–clathrin adaptor α/β/γ adaptin–β-adaptin appendage) predicted by AlphaFold2 to resemble both GGA vesicle adaptors and AP complex β-subunits; its transcription is down-regulated under metabolic stress and is positively regulated by the histone acetyltransferase PfGCN5 via direct promoter occupancy, while experimentally tested mutations in KIC4 do not confer artemisinin resistance and simultaneous disruption of KIC4 and KIC5 appears not tolerated."},"narrative":{"mechanistic_narrative":"KIC4 (PF3D7_1246300) is a K13 compartment protein of Plasmodium falciparum belonging to the subset of K13 compartment proteins carrying vesicle-trafficking domains [PMID:38039338]. AlphaFold2 modelling assigns it an unusual hybrid domain architecture — an N-terminal VHS domain, a GAT domain, a clathrin adaptor α/β/γ adaptin appendage domain typical of GGA vesicle adaptors, and an additional C-terminal β-adaptin appendage subdomain absent from GGAs — a combination not observed in any other protein and intermediate between GGA-type adaptors and AP-complex β-subunits [PMID:38039338]. Its transcription is stress-responsive and directly controlled: KIC4 mRNA is down-regulated under low-glucose stress, and the histone acetyltransferase PfGCN5 occupies the KIC4 5′ UTR promoter under stress in a manner lost upon PfGCN5 knockdown [PMID:37702516]. Functionally, engineered KIC4 mutations do not reduce artemisinin susceptibility in 3D7 parasites [PMID:38700363], and while KIC4 is individually dispensable, simultaneous disruption of KIC4 and KIC5 could not be achieved, consistent with a synthetically essential relationship between the two [PMID:38700363]. Beyond these findings — its domain architecture, transcriptional regulation, and genetic dispensability relationships — no direct experimental characterization of KIC4's molecular activity, binding partners, or role in endocytosis has been established in the available corpus.","teleology":[{"year":2023,"claim":"To place KIC4 within a functional module, it was assigned to the K13 compartment among proteins bearing vesicle-trafficking domains, framing it as a candidate trafficking adaptor rather than an uncharacterized ORF.","evidence":"Co-localisation with K13 (referencing prior BioID data) and computational domain classification in P. falciparum","pmids":["38039338"],"confidence":"Low","gaps":["Localization rests on prior BioID rather than a new experimental assay here","No direct functional assay linking KIC4 to endocytosis or artemisinin susceptibility","Membership in the K13 compartment does not define KIC4's specific molecular role"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"To infer what class of trafficking machinery KIC4 might represent, its structure was modelled, revealing a previously unseen hybrid of GGA-type adaptor and AP-complex β-subunit domains.","evidence":"AlphaFold2 prediction with RMSD-based alignment to PDB structures and InterPro domain annotation in P. falciparum","pmids":["38039338"],"confidence":"Low","gaps":["Purely computational — no in vitro validation of domain function or binding","No experimental demonstration of cargo, clathrin, or membrane interaction","The functional significance of the hybrid architecture is untested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"To determine how KIC4 expression is controlled, transcriptomic and chromatin approaches showed its down-regulation under metabolic stress and direct promoter occupancy by the acetyltransferase PfGCN5.","evidence":"RNA-seq under low-glucose stress plus ChIP-qPCR at the KIC4 5′ UTR in wild-type versus conditional PfGCN5 knockdown P. falciparum","pmids":["37702516"],"confidence":"Medium","gaps":["Functional consequence of KIC4 down-regulation for parasite physiology was not tested","Whether PfGCN5-dependent regulation reflects direct acetylation-linked activation at this locus is not resolved","No link established between stress-responsive expression and KIC4's trafficking role"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2024,"claim":"To test whether KIC4 contributes to artemisinin resistance like other K13 compartment members, engineered KIC4 mutations were assayed and found insufficient to reduce drug susceptibility.","evidence":"Selection-linked integration of a recodonized multi-mutant KIC4 sequence into 3D7 parasites followed by ring-stage survival assay with dihydroartemisinin","pmids":["38700363"],"confidence":"Medium","gaps":["Negative result from a single lab; other mutation combinations untested","Does not exclude a role for KIC4 in endocytosis independent of resistance","Tested within a multi-mutant construct, complicating attribution to KIC4 alone"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2024,"claim":"To probe KIC4's essentiality, disruption attempts showed it is individually dispensable but that combined KIC4/KIC5 loss could not be recovered, implying a synthetically lethal or redundant relationship.","evidence":"Six independent selection-linked-integration gene-disruption attempts per combination in P. falciparum 3D7","pmids":["38700363"],"confidence":"Low","gaps":["Inference from repeated failed transfections, not confirmed by conditional depletion or epistasis rescue","No mechanistic explanation of the KIC4/KIC5 interdependence","Whether KIC4 and KIC5 act in the same molecular process is not directly shown"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":null,"claim":"The direct molecular activity of KIC4 — whether its predicted hybrid adaptor domains bind cargo, clathrin, or membranes, and whether it functions in hemoglobin endocytosis — remains experimentally undefined.","evidence":"No direct biochemical or cell-biological assay of KIC4 function is present in the corpus","pmids":[],"confidence":"Low","gaps":["No demonstrated binding partners or cargo for KIC4","No experimental test of its predicted vesicle-adaptor function","Mechanistic basis of the KIC4/KIC5 synthetic relationship unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["K13 compartment"],"partners":["KIC5 (GENETIC INTERACTION / SYNTHETIC LETHALITY)","PFGCN5 (TRANSCRIPTIONAL REGULATOR OF KIC4 PROMOTER)"],"other_free_text":["Predicted hybrid domain architecture: VHS-GAT-clathrin adaptor appendage-β-adaptin appendage, intermediate between GGA adaptors and AP-complex β-subunits (AlphaFold2, [#0])","Transcription down-regulated under low-glucose metabolic stress; promoter directly occupied by PfGCN5 [#2]","Engineered KIC4 mutations do not confer artemisinin resistance in 3D7 [#3]","Individually dispensable but combined KIC4/KIC5 disruption not tolerated [#4]"]}},"prefetch_data":{},"corpus_meta":[{"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":["KIC4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37702516","id":"","title":"Plasmodium falciparum GCN5 plays a key role in regulating artemisinin resistance-related stress responses.","date":"2023","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/37702516","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KIC4"],"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":["KIC4"],"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":["KIC4"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7710,"output_tokens":1532,"usd":0.023055,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6618,"output_tokens":2780,"usd":0.051295,"stage2_stop_reason":"end_turn"},"total_usd":0.07435,"stage1_batch_id":"msgbatch_01NE1MTa8x1hW7Lo4tAaNzY1","stage2_batch_id":"msgbatch_0141vaQdeFvbo2q39AinvXM9","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"AlphaFold2 structural predictions revealed that KIC4 contains an unusual hybrid domain architecture: an N-terminal VHS domain, followed by a GAT domain, a clathrin adaptor α/β/γ adaptin appendage domain (typical of GGA vesicle adaptors), and an additional C-terminal β-adaptin appendage C-terminal subdomain not found in GGAs — a domain combination not previously observed in any other protein, suggesting KIC4 is a hybrid between GGA-type and AP complex β-subunit adaptors.\",\n      \"method\": \"AlphaFold2 structural prediction with domain comparison to PDB structures (RMSD-based alignment); domain annotation via InterPro\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational structural prediction only, no experimental validation of domain function or binding partners in vitro\",\n      \"pmids\": [\"38039338\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIC4 is a member of the K13 compartment and belongs to the group of K13 compartment proteins that contain vesicle trafficking domains; however, the paper does not report a specific functional assay establishing whether KIC4 influences endocytosis or ART susceptibility.\",\n      \"method\": \"Localization by co-localisation with K13 (prior BioID data referenced); domain classification by AlphaFold2 prediction\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — domain classification is computational; no direct experimental functional assay for KIC4 reported in this abstract\",\n      \"pmids\": [\"38039338\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIC4 gene expression is down-regulated under low glucose stress conditions in P. falciparum, and PfGCN5 occupancy at the KIC4 promoter (5′ UTR) is significantly enriched under stress conditions in wild-type parasites but not in PfGCN5 knockdown parasites, indicating that PfGCN5 regulates KIC4 transcription under stress.\",\n      \"method\": \"RNA-seq transcriptomics under stress conditions; chromatin-immunoprecipitation quantitative PCR (ChIP-qPCR) at the KIC4 5′ UTR in wild-type vs. TetR-DOZI conditional PfGCN5 knockdown parasites\",\n      \"journal\": \"Antimicrobial agents and chemotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (RNA-seq and ChIP-qPCR) in a single lab; direct promoter occupancy evidence supports transcriptional regulation, but functional consequence of KIC4 down-regulation itself was not tested\",\n      \"pmids\": [\"37702516\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Introduction of multiple non-synonymous mutations in KIC4 (as part of a multi-mutant construct tested by ring-stage survival assay) did not confer ART resistance in P. falciparum 3D7 parasites, indicating that the tested KIC4 mutations are not sufficient to reduce artemisinin susceptibility.\",\n      \"method\": \"Selection-linked integration to introduce multi-mutant recodonized KIC4 sequence into 3D7 parasites; ring-stage survival assay (RSA) with dihydroartemisinin\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic approach with RSA functional readout, but this is a negative result and a single lab study\",\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) repeatedly failed across six independent attempts each, suggesting that combined loss of KIC4 and KIC5 is not tolerated, implying each is individually dispensable but together essential or synthetically lethal.\",\n      \"method\": \"Selection-linked integration-based gene disruption attempts (six independent attempts per combination) in P. falciparum\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — inference from failed genetic experiments (negative result interpreted as synthetic lethality); no direct rescue or epistasis confirmation\",\n      \"pmids\": [\"38700363\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    }\n  ],\n  \"current_model\": \"KIC4 (PF3D7_1246300) is a P. falciparum K13 compartment protein with a unique hybrid domain architecture (VHS–GAT–clathrin adaptor α/β/γ adaptin–β-adaptin appendage) predicted by AlphaFold2 to resemble both GGA vesicle adaptors and AP complex β-subunits; its transcription is down-regulated under metabolic stress and is positively regulated by the histone acetyltransferase PfGCN5 via direct promoter occupancy, while experimentally tested mutations in KIC4 do not confer artemisinin resistance and simultaneous disruption of KIC4 and KIC5 appears not tolerated.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIC4 (PF3D7_1246300) is a K13 compartment protein of Plasmodium falciparum belonging to the subset of K13 compartment proteins carrying vesicle-trafficking domains [#1]. AlphaFold2 modelling assigns it an unusual hybrid domain architecture — an N-terminal VHS domain, a GAT domain, a clathrin adaptor \\u03b1/\\u03b2/\\u03b3 adaptin appendage domain typical of GGA vesicle adaptors, and an additional C-terminal \\u03b2-adaptin appendage subdomain absent from GGAs — a combination not observed in any other protein and intermediate between GGA-type adaptors and AP-complex \\u03b2-subunits [#0]. Its transcription is stress-responsive and directly controlled: KIC4 mRNA is down-regulated under low-glucose stress, and the histone acetyltransferase PfGCN5 occupies the KIC4 5\\u2032 UTR promoter under stress in a manner lost upon PfGCN5 knockdown [#2]. Functionally, engineered KIC4 mutations do not reduce artemisinin susceptibility in 3D7 parasites [#3], and while KIC4 is individually dispensable, simultaneous disruption of KIC4 and KIC5 could not be achieved, consistent with a synthetically essential relationship between the two [#4]. Beyond these findings — its domain architecture, transcriptional regulation, and genetic dispensability relationships — no direct experimental characterization of KIC4's molecular activity, binding partners, or role in endocytosis has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"To place KIC4 within a functional module, it was assigned to the K13 compartment among proteins bearing vesicle-trafficking domains, framing it as a candidate trafficking adaptor rather than an uncharacterized ORF.\",\n      \"evidence\": \"Co-localisation with K13 (referencing prior BioID data) and computational domain classification in P. falciparum\",\n      \"pmids\": [\"38039338\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization rests on prior BioID rather than a new experimental assay here\", \"No direct functional assay linking KIC4 to endocytosis or artemisinin susceptibility\", \"Membership in the K13 compartment does not define KIC4's specific molecular role\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To infer what class of trafficking machinery KIC4 might represent, its structure was modelled, revealing a previously unseen hybrid of GGA-type adaptor and AP-complex \\u03b2-subunit domains.\",\n      \"evidence\": \"AlphaFold2 prediction with RMSD-based alignment to PDB structures and InterPro domain annotation in P. falciparum\",\n      \"pmids\": [\"38039338\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Purely computational — no in vitro validation of domain function or binding\", \"No experimental demonstration of cargo, clathrin, or membrane interaction\", \"The functional significance of the hybrid architecture is untested\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To determine how KIC4 expression is controlled, transcriptomic and chromatin approaches showed its down-regulation under metabolic stress and direct promoter occupancy by the acetyltransferase PfGCN5.\",\n      \"evidence\": \"RNA-seq under low-glucose stress plus ChIP-qPCR at the KIC4 5\\u2032 UTR in wild-type versus conditional PfGCN5 knockdown P. falciparum\",\n      \"pmids\": [\"37702516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of KIC4 down-regulation for parasite physiology was not tested\", \"Whether PfGCN5-dependent regulation reflects direct acetylation-linked activation at this locus is not resolved\", \"No link established between stress-responsive expression and KIC4's trafficking role\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To test whether KIC4 contributes to artemisinin resistance like other K13 compartment members, engineered KIC4 mutations were assayed and found insufficient to reduce drug susceptibility.\",\n      \"evidence\": \"Selection-linked integration of a recodonized multi-mutant KIC4 sequence into 3D7 parasites followed by ring-stage survival assay with dihydroartemisinin\",\n      \"pmids\": [\"38700363\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result from a single lab; other mutation combinations untested\", \"Does not exclude a role for KIC4 in endocytosis independent of resistance\", \"Tested within a multi-mutant construct, complicating attribution to KIC4 alone\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To probe KIC4's essentiality, disruption attempts showed it is individually dispensable but that combined KIC4/KIC5 loss could not be recovered, implying a synthetically lethal or redundant relationship.\",\n      \"evidence\": \"Six independent selection-linked-integration gene-disruption attempts per combination in P. falciparum 3D7\",\n      \"pmids\": [\"38700363\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Inference from repeated failed transfections, not confirmed by conditional depletion or epistasis rescue\", \"No mechanistic explanation of the KIC4/KIC5 interdependence\", \"Whether KIC4 and KIC5 act in the same molecular process is not directly shown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular activity of KIC4 — whether its predicted hybrid adaptor domains bind cargo, clathrin, or membranes, and whether it functions in hemoglobin endocytosis — remains experimentally undefined.\",\n      \"evidence\": \"No direct biochemical or cell-biological assay of KIC4 function is present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No demonstrated binding partners or cargo for KIC4\", \"No experimental test of its predicted vesicle-adaptor function\", \"Mechanistic basis of the KIC4/KIC5 synthetic relationship unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030276\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016192\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"K13 compartment\"],\n    \"partners\": [\"KIC5 (genetic interaction / synthetic lethality)\", \"PfGCN5 (transcriptional regulator of KIC4 promoter)\"],\n    \"other_free_text\": [\n      \"Predicted hybrid domain architecture: VHS-GAT-clathrin adaptor appendage-\\u03b2-adaptin appendage, intermediate between GGA adaptors and AP-complex \\u03b2-subunits (AlphaFold2, [#0])\",\n      \"Transcription down-regulated under low-glucose metabolic stress; promoter directly occupied by PfGCN5 [#2]\",\n      \"Engineered KIC4 mutations do not confer artemisinin resistance in 3D7 [#3]\",\n      \"Individually dispensable but combined KIC4/KIC5 disruption not tolerated [#4]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1246300","name":null,"product":"protein KIC4","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1459400","name":null,"product":"clathrin adaptor domain-containing protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1466000","name":null,"product":"clathrin adaptor domain-containing protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"KIC4","evaluation":null}