{"gene":"PF3D7_0201800","run_date":"2026-09-08T16:26:55","timeline":{"discoveries":[{"year":2012,"finding":"KAHsp40 (PF3D7_0201800) contains a PEXEL motif and is exported to the erythrocyte cytoplasm in a stage-dependent manner, localizing as punctate spots at the erythrocyte periphery distinct from Maurer's clefts, in structures consistent with knobs, as shown by subcellular fractionation and immunofluorescence analysis.","method":"Subcellular fractionation and immunofluorescence analysis (IFA)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (stage-dependent export, knob co-localization), single lab, two orthogonal methods (fractionation + IFA)","pmids":["22970262"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"KAHsp40 (PF3D7_0201800) co-localizes with knob markers KAHRP, PfEMP1, and PfEMP3, and with PTEX components Hsp101 and PTEX150, as shown by double immunofluorescence analysis.","method":"Double immunofluorescence analysis (co-localization)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization by IFA with multiple markers, single lab, consistent across several markers","pmids":["22970262"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"KAHsp40 (PF3D7_0201800) is found in a protein complex with KAHRP, PfEMP3, and Hsp101, as confirmed by co-immunoprecipitation assay.","method":"Co-immunoprecipitation (Co-IP)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP experiment, single lab, but consistent with IFA co-localization data from the same study","pmids":["22970262"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"The gene encoding KAHsp40 (PF3D7_0201800) is located in a chromosomal cluster on chromosome 2 together with knob components KAHRP and PfEMP3, suggesting co-regulation.","method":"Genomic sequence analysis / chromosomal mapping","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 / Weak — genomic/bioinformatic observation only, no functional experiment directly testing the co-regulation consequence","pmids":["22970262"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"finding":"The J-domain of KAHsp40 (PF3D7_0201800/PFB0090c) stimulates the ATPase activity of PfHSP70-X, human HsHSP70, and HsHSC70 in vitro, consistent with its classification as a Type II J-domain protein with an intact HPD motif.","method":"In vitro ATPase activity assay using isolated J-domain","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution assay, but KAHsp40 is one of three proteins tested and results are not individually highlighted for it; single lab, single method","pmids":["41618743"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"KAHsp40 (PF3D7_0201800) gene locus shows increased HP1 (heterochromatin protein 1) occupancy in gametocytes compared to asexual schizonts, indicating epigenetic silencing of KAHsp40 expression during sexual differentiation.","method":"ChIP-seq for HP1 occupancy across life cycle stages","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with clear locus-specific data shown, single lab but rigorous methodology","pmids":["29503181"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"Pf2004"}]},{"year":2021,"finding":"KAHsp40 (PF3D7_0201800) is enriched with repressive H3K36me2 and H3K36me3 histone marks in stage II gametocytes, and is co-occupied by HP1, indicating cooperative epigenetic repression of KAHsp40 during early gametocyte development.","method":"ChIP-seq for H3K36me2 and H3K36me3 in stage II gametocytes","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with locus-specific data, single lab, consistent with HP1 data from independent study","pmids":["33794978"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"KAHsp40 (PF3D7_0201800) is a PEXEL-containing Hsp40/J-domain protein exported from P. falciparum to the infected erythrocyte cytoplasm, where it localizes to knob structures (distinct from Maurer's clefts), forms a complex with knob components KAHRP and PfEMP3 and the PTEX component Hsp101, and its isolated J-domain can stimulate HSP70 ATPase activity in vitro; its gene locus is epigenetically silenced by HP1 and H3K36me2/3 during gametocyte development, consistent with a function restricted to asexual-stage knob assembly and cytoadherence."},"narrative":{"mechanistic_narrative":"KAHsp40 (PF3D7_0201800) is a PEXEL-containing Hsp40/J-domain co-chaperone that Plasmodium falciparum exports into the infected erythrocyte cytoplasm during the asexual blood stage, where it localizes to punctate peripheral structures consistent with knobs and distinct from Maurer's clefts [PMID:22970262]. At these sites it co-localizes with the knob components KAHRP, PfEMP1, and PfEMP3 and with the PTEX translocon components Hsp101 and PTEX150, and biochemically forms a complex with KAHRP, PfEMP3, and Hsp101, placing it within the knob-assembly/cytoadherence machinery of the host cell [PMID:22970262]. Functionally, its isolated J-domain retains an intact HPD motif and stimulates the ATPase activity of HSP70 chaperones in vitro, consistent with a canonical Type II J-protein co-chaperone activity [PMID:41618743]. Consistent with a role restricted to the asexual stage, the KAHsp40 locus is epigenetically silenced during sexual differentiation, acquiring HP1 occupancy and repressive H3K36me2/3 marks in gametocytes [PMID:29503181, PMID:33794978]. Beyond these findings, the specific contribution of KAHsp40's chaperone activity to knob morphogenesis and the direct nature of its complex partnerships have not been further characterized in the available corpus.","teleology":[{"year":2012,"claim":"Establishing that KAHsp40 is not retained in the parasite but reaches the host cell answered where this J-protein acts, defining it as an exported effector targeted to knob-like structures rather than to Maurer's clefts.","evidence":"Subcellular fractionation and immunofluorescence tracking a PEXEL-containing protein across blood-stage development","pmids":["22970262"],"confidence":"Medium","gaps":["Direct demonstration that PEXEL cleavage/processing drives export was not shown","Whether localization is to bona fide knobs versus another peripheral compartment rests on marker co-localization","No knockout/knockdown to test functional requirement for export"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Co-localization and co-immunoprecipitation with knob and PTEX components addressed which machinery KAHsp40 associates with, embedding it in the knob-assembly complex and linking it to the export translocon.","evidence":"Double IFA with KAHRP, PfEMP1, PfEMP3, Hsp101, PTEX150 and Co-IP recovering KAHRP, PfEMP3, and Hsp101","pmids":["22970262"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal pull-downs; direct versus indirect interactions not resolved","Stoichiometry and architecture of the complex unknown","No functional consequence of complex disruption tested"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Mapping the locus alongside KAHRP and PfEMP3 on chromosome 2 raised the possibility of co-regulation of knob-component genes, though it is a genomic observation only.","evidence":"Genomic sequence analysis / chromosomal mapping","pmids":["22970262"],"confidence":"Low","gaps":["Bioinformatic observation only; no experiment testing shared regulation","No transcriptional or chromatin data linking the clustered genes at this stage"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"ChIP-seq showing HP1 gain at the locus in gametocytes answered how KAHsp40 expression is switched off outside the asexual stage, indicating heterochromatin-based silencing during sexual differentiation.","evidence":"HP1 ChIP-seq comparing gametocytes to asexual schizonts","pmids":["29503181"],"confidence":"Medium","gaps":["Correlates chromatin state with silencing but does not directly measure KAHsp40 transcript loss","Mechanistic trigger for HP1 deposition at this locus unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":"Pf2004"}]},{"year":2021,"claim":"Detection of repressive H3K36me2/3 co-occurring with HP1 in stage II gametocytes refined the silencing model, indicating cooperative histone-mark and HP1-based repression early in gametocyte development.","evidence":"H3K36me2/H3K36me3 ChIP-seq in stage II gametocytes","pmids":["33794978"],"confidence":"Medium","gaps":["Causal role of the histone marks in silencing not tested by perturbation","Order and interdependence of HP1 and H3K36 methylation unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"claim":"In vitro ATPase assays with the isolated J-domain addressed whether KAHsp40 is a functional co-chaperone, showing it can stimulate parasite and human HSP70 ATPase activity as a Type II J-protein.","evidence":"In vitro ATPase activity assay using the isolated J-domain against PfHSP70-X, HsHSP70, and HsHSC70","pmids":["41618743"],"confidence":"Medium","gaps":["Tested as one of three J-proteins; KAHsp40-specific results not individually highlighted","Isolated domain only; full-length activity and physiological HSP70 partner in the erythrocyte not established","No link demonstrated between chaperone activity and knob assembly"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether KAHsp40's co-chaperone activity is functionally required for knob morphogenesis, PfEMP1 display, and cytoadherence, and which HSP70 it partners with in vivo, remains unresolved.","evidence":"No loss-of-function or in vivo partnering study present in the corpus","pmids":[],"confidence":"Low","gaps":["No genetic knockout/knockdown phenotype reported","In vivo HSP70 partner at the knob unidentified","Direct role in cytoadherence not demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Knob-associated complex with KAHRP, PfEMP3, and Hsp101 (Co-IP) [#2]"],"partners":["KAHRP [#1, #2]","PFEMP3 [#1, #2]","PFEMP1 (CO-LOCALIZATION) [#1]","HSP101/PTEX [#1, #2]","PTEX150 (CO-LOCALIZATION) [#1]","PFHSP70-X (IN VITRO ATPASE STIMULATION) [#4]","HSHSP70 / HSHSC70 (IN VITRO ATPASE STIMULATION) [#4]"],"other_free_text":["PEXEL-containing exported protein released into the infected erythrocyte cytoplasm in a stage-dependent manner [#0]","Type II J-domain protein with an intact HPD motif [#4]","Gene locus epigenetically silenced in gametocytes via HP1 occupancy and repressive H3K36me2/3 marks, consistent with asexual-stage-restricted expression [#5, #6]","Gene clustered on chromosome 2 with KAHRP and PfEMP3 [#3]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"22970262","id":"PMC_22970262","title":"An exported heat shock protein 40 associates with pathogenesis-related knobs in Plasmodium falciparum infected erythrocytes.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22970262","citation_count":38,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40","PFB0090c"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41607793","id":"","title":"Antibody levels to variant and conserved Plasmodium falciparum antigens predict reduction in parasite burden in Malian children.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41607793","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39829323","id":"","title":"A Systematic Targeted Genetic Screen Identifies Proteins Involved in Cytoadherence of the Malaria Parasite P. falciparum.","date":"2025","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39829323","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41618743","id":"","title":"Promiscuous stimulation of HSP70 ATPase activity by parasite-derived J-domains.","date":"2026","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/41618743","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38518861","id":"","title":"Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update.","date":"2024","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/38518861","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38146350","id":"","title":"Comparative analysis of peripheral whole blood transcriptome from asymptomatic carriers reveals upregulation of subsets of surface proteins implicated in Plasmodium falciparum phenotypic plasticity.","date":"2023","source":"Biochemistry and biophysics reports","url":"https://pubmed.ncbi.nlm.nih.gov/38146350","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35652103","id":"","title":"Plasmodium falciparum Molecular Chaperones: Guardians of the Malaria Parasite Proteome and Renovators of the Host Proteome.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35652103","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36120546","id":"","title":"Exported J domain proteins of the human malaria parasite.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36120546","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37457831","id":"","title":"The Plasmodium falciparum exported J domain proteins fine-tune human and malarial Hsp70s: pathological exploitation of proteostasis machinery.","date":"2023","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/37457831","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31795940","id":"","title":"Hierarchical transcriptional control regulates Plasmodium falciparum sexual differentiation.","date":"2019","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31795940","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"33794978","id":"","title":"H3K36 methylation reprograms gene expression to drive early gametocyte development in Plasmodium falciparum.","date":"2021","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/33794978","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29503181","id":"","title":"Comparative Heterochromatin Profiling Reveals Conserved and Unique Epigenome Signatures Linked to Adaptation and Development of Malaria Parasites.","date":"2018","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/29503181","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29529020","id":"","title":"The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen-encoding var genes.","date":"2018","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/29529020","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23340228","id":"","title":"Identification of an exported heat shock protein 70 in Plasmodium falciparum.","date":"2013","source":"Parasite (Paris, France)","url":"https://pubmed.ncbi.nlm.nih.gov/23340228","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25726759","id":"","title":"Dynamic association of PfEMP1 and KAHRP in knobs mediates cytoadherence during Plasmodium invasion.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25726759","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["KAHsp40"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17692,"output_tokens":1787,"usd":0.03994,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6827,"output_tokens":3178,"usd":0.056793,"stage2_stop_reason":"end_turn"},"total_usd":0.096733,"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\": 2012,\n      \"finding\": \"KAHsp40 (PF3D7_0201800) contains a PEXEL motif and is exported to the erythrocyte cytoplasm in a stage-dependent manner, localizing as punctate spots at the erythrocyte periphery distinct from Maurer's clefts, in structures consistent with knobs, as shown by subcellular fractionation and immunofluorescence analysis.\",\n      \"method\": \"Subcellular fractionation and immunofluorescence analysis (IFA)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (stage-dependent export, knob co-localization), single lab, two orthogonal methods (fractionation + IFA)\",\n      \"pmids\": [\"22970262\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KAHsp40 (PF3D7_0201800) co-localizes with knob markers KAHRP, PfEMP1, and PfEMP3, and with PTEX components Hsp101 and PTEX150, as shown by double immunofluorescence analysis.\",\n      \"method\": \"Double immunofluorescence analysis (co-localization)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization by IFA with multiple markers, single lab, consistent across several markers\",\n      \"pmids\": [\"22970262\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KAHsp40 (PF3D7_0201800) is found in a protein complex with KAHRP, PfEMP3, and Hsp101, as confirmed by co-immunoprecipitation assay.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP experiment, single lab, but consistent with IFA co-localization data from the same study\",\n      \"pmids\": [\"22970262\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The gene encoding KAHsp40 (PF3D7_0201800) is located in a chromosomal cluster on chromosome 2 together with knob components KAHRP and PfEMP3, suggesting co-regulation.\",\n      \"method\": \"Genomic sequence analysis / chromosomal mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — genomic/bioinformatic observation only, no functional experiment directly testing the co-regulation consequence\",\n      \"pmids\": [\"22970262\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The J-domain of KAHsp40 (PF3D7_0201800/PFB0090c) stimulates the ATPase activity of PfHSP70-X, human HsHSP70, and HsHSC70 in vitro, consistent with its classification as a Type II J-domain protein with an intact HPD motif.\",\n      \"method\": \"In vitro ATPase activity assay using isolated J-domain\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution assay, but KAHsp40 is one of three proteins tested and results are not individually highlighted for it; single lab, single method\",\n      \"pmids\": [\"41618743\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KAHsp40 (PF3D7_0201800) gene locus shows increased HP1 (heterochromatin protein 1) occupancy in gametocytes compared to asexual schizonts, indicating epigenetic silencing of KAHsp40 expression during sexual differentiation.\",\n      \"method\": \"ChIP-seq for HP1 occupancy across life cycle stages\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with clear locus-specific data shown, single lab but rigorous methodology\",\n      \"pmids\": [\"29503181\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Pf2004\"}]\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAHsp40 (PF3D7_0201800) is enriched with repressive H3K36me2 and H3K36me3 histone marks in stage II gametocytes, and is co-occupied by HP1, indicating cooperative epigenetic repression of KAHsp40 during early gametocyte development.\",\n      \"method\": \"ChIP-seq for H3K36me2 and H3K36me3 in stage II gametocytes\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with locus-specific data, single lab, consistent with HP1 data from independent study\",\n      \"pmids\": [\"33794978\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"KAHsp40 (PF3D7_0201800) is a PEXEL-containing Hsp40/J-domain protein exported from P. falciparum to the infected erythrocyte cytoplasm, where it localizes to knob structures (distinct from Maurer's clefts), forms a complex with knob components KAHRP and PfEMP3 and the PTEX component Hsp101, and its isolated J-domain can stimulate HSP70 ATPase activity in vitro; its gene locus is epigenetically silenced by HP1 and H3K36me2/3 during gametocyte development, consistent with a function restricted to asexual-stage knob assembly and cytoadherence.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KAHsp40 (PF3D7_0201800) is a PEXEL-containing Hsp40/J-domain co-chaperone that Plasmodium falciparum exports into the infected erythrocyte cytoplasm during the asexual blood stage, where it localizes to punctate peripheral structures consistent with knobs and distinct from Maurer's clefts [#0]. At these sites it co-localizes with the knob components KAHRP, PfEMP1, and PfEMP3 and with the PTEX translocon components Hsp101 and PTEX150, and biochemically forms a complex with KAHRP, PfEMP3, and Hsp101, placing it within the knob-assembly/cytoadherence machinery of the host cell [#1, #2]. Functionally, its isolated J-domain retains an intact HPD motif and stimulates the ATPase activity of HSP70 chaperones in vitro, consistent with a canonical Type II J-protein co-chaperone activity [#4]. Consistent with a role restricted to the asexual stage, the KAHsp40 locus is epigenetically silenced during sexual differentiation, acquiring HP1 occupancy and repressive H3K36me2/3 marks in gametocytes [#5, #6]. Beyond these findings, the specific contribution of KAHsp40's chaperone activity to knob morphogenesis and the direct nature of its complex partnerships have not been further characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that KAHsp40 is not retained in the parasite but reaches the host cell answered where this J-protein acts, defining it as an exported effector targeted to knob-like structures rather than to Maurer's clefts.\",\n      \"evidence\": \"Subcellular fractionation and immunofluorescence tracking a PEXEL-containing protein across blood-stage development\",\n      \"pmids\": [\"22970262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct demonstration that PEXEL cleavage/processing drives export was not shown\",\n        \"Whether localization is to bona fide knobs versus another peripheral compartment rests on marker co-localization\",\n        \"No knockout/knockdown to test functional requirement for export\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Co-localization and co-immunoprecipitation with knob and PTEX components addressed which machinery KAHsp40 associates with, embedding it in the knob-assembly complex and linking it to the export translocon.\",\n      \"evidence\": \"Double IFA with KAHRP, PfEMP1, PfEMP3, Hsp101, PTEX150 and Co-IP recovering KAHRP, PfEMP3, and Hsp101\",\n      \"pmids\": [\"22970262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single Co-IP without reciprocal pull-downs; direct versus indirect interactions not resolved\",\n        \"Stoichiometry and architecture of the complex unknown\",\n        \"No functional consequence of complex disruption tested\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Mapping the locus alongside KAHRP and PfEMP3 on chromosome 2 raised the possibility of co-regulation of knob-component genes, though it is a genomic observation only.\",\n      \"evidence\": \"Genomic sequence analysis / chromosomal mapping\",\n      \"pmids\": [\"22970262\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Bioinformatic observation only; no experiment testing shared regulation\",\n        \"No transcriptional or chromatin data linking the clustered genes at this stage\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ChIP-seq showing HP1 gain at the locus in gametocytes answered how KAHsp40 expression is switched off outside the asexual stage, indicating heterochromatin-based silencing during sexual differentiation.\",\n      \"evidence\": \"HP1 ChIP-seq comparing gametocytes to asexual schizonts\",\n      \"pmids\": [\"29503181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlates chromatin state with silencing but does not directly measure KAHsp40 transcript loss\",\n        \"Mechanistic trigger for HP1 deposition at this locus unknown\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"Pf2004\"}]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Detection of repressive H3K36me2/3 co-occurring with HP1 in stage II gametocytes refined the silencing model, indicating cooperative histone-mark and HP1-based repression early in gametocyte development.\",\n      \"evidence\": \"H3K36me2/H3K36me3 ChIP-seq in stage II gametocytes\",\n      \"pmids\": [\"33794978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal role of the histone marks in silencing not tested by perturbation\",\n        \"Order and interdependence of HP1 and H3K36 methylation unresolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"In vitro ATPase assays with the isolated J-domain addressed whether KAHsp40 is a functional co-chaperone, showing it can stimulate parasite and human HSP70 ATPase activity as a Type II J-protein.\",\n      \"evidence\": \"In vitro ATPase activity assay using the isolated J-domain against PfHSP70-X, HsHSP70, and HsHSC70\",\n      \"pmids\": [\"41618743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Tested as one of three J-proteins; KAHsp40-specific results not individually highlighted\",\n        \"Isolated domain only; full-length activity and physiological HSP70 partner in the erythrocyte not established\",\n        \"No link demonstrated between chaperone activity and knob assembly\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether KAHsp40's co-chaperone activity is functionally required for knob morphogenesis, PfEMP1 display, and cytoadherence, and which HSP70 it partners with in vivo, remains unresolved.\",\n      \"evidence\": \"No loss-of-function or in vivo partnering study present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic knockout/knockdown phenotype reported\",\n        \"In vivo HSP70 partner at the knob unidentified\",\n        \"Direct role in cytoadherence not demonstrated\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001671\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0051087\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020030\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0020036\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0052192\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0006325\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\n      \"Knob-associated complex with KAHRP, PfEMP3, and Hsp101 (Co-IP) [#2]\"\n    ],\n    \"partners\": [\n      \"KAHRP [#1, #2]\",\n      \"PfEMP3 [#1, #2]\",\n      \"PfEMP1 (co-localization) [#1]\",\n      \"Hsp101/PTEX [#1, #2]\",\n      \"PTEX150 (co-localization) [#1]\",\n      \"PfHSP70-X (in vitro ATPase stimulation) [#4]\",\n      \"HsHSP70 / HsHSC70 (in vitro ATPase stimulation) [#4]\"\n    ],\n    \"other_free_text\": [\n      \"PEXEL-containing exported protein released into the infected erythrocyte cytoplasm in a stage-dependent manner [#0]\",\n      \"Type II J-domain protein with an intact HPD motif [#4]\",\n      \"Gene locus epigenetically silenced in gametocytes via HP1 occupancy and repressive H3K36me2/3 marks, consistent with asexual-stage-restricted expression [#5, #6]\",\n      \"Gene clustered on chromosome 2 with KAHRP and PfEMP3 [#3]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0201800","name":null,"product":"knob associated heat shock protein 40","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"KAHsp40","evaluation":null}