{"gene":"PF3D7_1134000","run_date":"2026-09-08T12:51:28","timeline":{"discoveries":[{"year":2016,"finding":"PfHsp70-3 (PF3D7_1134000), the sole Hsp70 predicted to localize to the P. falciparum mitochondria, undergoes self-aggregation that is specifically suppressed by co-expression with PfHep1 (a Hsp70-escort protein orthologue). Co-expression of PfHsp70-3 with PfHep1 enhanced PfHsp70-3 solubility, and purified PfHep1 suppressed thermally induced aggregation of PfHsp70-3 but not of malate dehydrogenase or citrate synthase, demonstrating substrate specificity. Zinc ions were essential for PfHep1 function, as EDTA chelation abrogated its ability to prevent PfHsp70-3 aggregation.","method":"Co-expression in E. coli (solubility assay), in vitro thermal aggregation suppression assay with purified proteins, EDTA chelation to assess zinc dependence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro methods (co-expression solubility, aggregation suppression, zinc chelation) in a single focused study on this specific protein, single lab","pmids":["27253881"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1134000 (HSP70-3) is the sole mitochondrially predicted Hsp70 of P. falciparum; it is prone to self-aggregation and requires the zinc-dependent escort protein PfHep1 to maintain its solubility and prevent thermal aggregation, indicating that PfHep1 is an obligate cochaperone for PfHsp70-3 function in the mitochondria."},"narrative":{"mechanistic_narrative":"PF3D7_1134000 (HSP70-3) is the sole Hsp70 chaperone predicted to localize to the mitochondrion of Plasmodium falciparum [PMID:27253881]. Purified PfHsp70-3 is intrinsically prone to self-aggregation, and this aggregation is specifically suppressed by the Hsp70-escort protein PfHep1: co-expression with PfHep1 in E. coli enhances PfHsp70-3 solubility, and purified PfHep1 prevents thermally induced aggregation of PfHsp70-3 but not of unrelated substrates such as malate dehydrogenase or citrate synthase, establishing substrate specificity [PMID:27253881]. PfHep1 function depends on zinc, as EDTA chelation abolishes its ability to keep PfHsp70-3 soluble, indicating that a zinc-dependent escort chaperone is required to maintain the folding-competent, non-aggregated state of PfHsp70-3 [PMID:27253881]. Beyond this escort relationship, no substrate specificity, ATPase activity, cochaperone network, or in vivo mitochondrial function of PF3D7_1134000 has been characterized in the available corpus.","teleology":[{"year":2016,"claim":"It was unknown how the aggregation-prone, mitochondrially predicted Plasmodium Hsp70 is maintained in a soluble state; this work showed that the escort protein PfHep1 specifically and zinc-dependently prevents PfHsp70-3 self-aggregation, establishing PfHep1 as an obligate cochaperone for PfHsp70-3 solubility.","evidence":"Co-expression solubility assay in E. coli plus in vitro thermal aggregation suppression with purified proteins and EDTA zinc chelation","pmids":["27253881"],"confidence":"Medium","gaps":["The in vivo mitochondrial localization and physiological function of PfHsp70-3 in the parasite were not tested","No client/substrate proteins of PfHsp70-3 or its ATPase/refolding activity were characterized","The stoichiometry and structural basis of the PfHsp70-3–PfHep1 interaction were not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"Whether PfHsp70-3 acts as a functional folding chaperone in the parasite mitochondrion, what its substrates and nucleotide-exchange/J-domain cochaperones are, and whether the PfHep1 dependence is essential in vivo remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vivo genetic or localization data for PF3D7_1134000 in the corpus","No identified physiological substrates or partner chaperones beyond PfHep1","No structural model of PfHsp70-3 or the escort complex"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFHEP1 (HSP70-ESCORT PROTEIN; ZINC-DEPENDENT, SUPPRESSES PFHSP70-3 AGGREGATION) [#0]"],"other_free_text":["PfHsp70-3 is the sole Hsp70 predicted to localize to the P. falciparum mitochondrion [#0]","PfHsp70-3 is intrinsically prone to self-aggregation in vitro [#0]","PfHep1-mediated protection of PfHsp70-3 is zinc-dependent and abolished by EDTA [#0]","PfHep1 substrate specificity demonstrated: it suppresses PfHsp70-3 but not malate dehydrogenase or citrate synthase aggregation [#0]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"8153120","id":"PMC_8153120","title":"Demonstration of heat-shock protein 70 in the sporozoite stage of malaria parasites.","date":"1994","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/8153120","citation_count":182,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"3095842","id":"PMC_3095842","title":"A repetitive antigen of Plasmodium falciparum that is homologous to heat shock protein 70 of Drosophila melanogaster.","date":"1986","source":"Proceedings of the National 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research","url":"https://pubmed.ncbi.nlm.nih.gov/8475027","citation_count":22,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24013507","id":"PMC_24013507","title":"Expression profiling of Plasmodium berghei HSP70 genes for generation of bright red fluorescent parasites.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24013507","citation_count":21,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25701168","id":"PMC_25701168","title":"PFB0595w is a Plasmodium falciparum J protein that co-localizes with PfHsp70-1 and can stimulate its in vitro ATP hydrolysis activity.","date":"2015","source":"The international journal of biochemistry & cell 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chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/34023985","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9010839","id":"PMC_9010839","title":"Further characterization of a 58 kDa Plasmodium berghei phosphoprotein as a cochaperone.","date":"1996","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9010839","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37457831","id":"PMC_37457831","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 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39549508","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38734650","id":"PMC_38734650","title":"Phytochemical evaluation of Ziziphus mucronata and Xysmalobium undulutum towards the discovery and development of anti-malarial drugs.","date":"2024","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/38734650","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"19523215","id":"PMC_19523215","title":"The effect of mimicking febrile temperature and drug stress on malarial development.","date":"2009","source":"Annals of clinical microbiology and antimicrobials","url":"https://pubmed.ncbi.nlm.nih.gov/19523215","citation_count":3,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38460641","id":"PMC_38460641","title":"Understanding the complex formation of falstatin; an endogenous macromolecular inhibitor of falcipains.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38460641","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"8167001","id":"PMC_8167001","title":"Serine-stretch protein (SERP) of Plasmodium falciparum corresponds to the exoantigen Ag2, a target of antibodies associated with protection against malaria.","date":"1994","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/8167001","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38500145","id":"PMC_38500145","title":"Iso-mukaadial acetate and ursolic acid acetate bind to Plasmodium Falciparum heat shock protein 70: towards targeting parasite protein folding pathway.","date":"2024","source":"BMC chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38500145","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41011525","id":"PMC_41011525","title":"Acanthospermum australe Extract Inhibits the Chaperone Activity of Plasmodium falciparum Heat Shock Protein 70-1.","date":"2025","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/41011525","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41864451","id":"PMC_41864451","title":"Flow cytometry-based evaluation of hepatic infection by non-fluorescent Plasmodium parasites.","date":"2026","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/41864451","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"42390429","id":"PMC_42390429","title":"Development of domain-specific probes of Plasmodium falciparum heat shock protein 70-1.","date":"2026","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/42390429","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12563736","id":"PMC_12563736","title":"[Finding of new FCC1/HN antigenic expressed sequence tag(ESTs) of Plasmodium falciparum].","date":"1999","source":"Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/12563736","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["heat shock protein 70"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25416,"output_tokens":808,"usd":0.044184,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5037,"output_tokens":1586,"usd":0.032418,"stage2_stop_reason":"end_turn"},"total_usd":0.076602,"stage1_batch_id":"msgbatch_01DisAaTypwmC8QwdMBuePHo","stage2_batch_id":"msgbatch_0184zxZTqxiEfdYYfPMfkqjb","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully identify which papers are about PF3D7_1134000 (HSP70-3), the mitochondrial Hsp70 of P. falciparum. \n\nKey point: The corpus is dominated by papers about **PfHsp70-1** (the major cytosolic Hsp70, PF3D7_0818900) and other family members. PF3D7_1134000/HSP70-3 is specifically the **mitochondrial** Hsp70 of P. falciparum. I must only extract findings about HSP70-3/PF3D7_1134000 itself.\n\nAfter reviewing all 43 papers:\n\n- Paper [33] (PMID 27253881) is the ONLY paper specifically about PfHsp70-3 (PF3D7_1134000). It studies PfHsp70-3 and its interaction with PfHep1.\n- All other papers predominantly discuss PfHsp70-1, PfHsp70-2 (GRP78/BiP), PfHsp70-x, or the family broadly, with no specific mechanistic findings attributed to HSP70-3/PF3D7_1134000.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"PfHsp70-3 (PF3D7_1134000), the sole Hsp70 predicted to localize to the P. falciparum mitochondria, undergoes self-aggregation that is specifically suppressed by co-expression with PfHep1 (a Hsp70-escort protein orthologue). Co-expression of PfHsp70-3 with PfHep1 enhanced PfHsp70-3 solubility, and purified PfHep1 suppressed thermally induced aggregation of PfHsp70-3 but not of malate dehydrogenase or citrate synthase, demonstrating substrate specificity. Zinc ions were essential for PfHep1 function, as EDTA chelation abrogated its ability to prevent PfHsp70-3 aggregation.\",\n      \"method\": \"Co-expression in E. coli (solubility assay), in vitro thermal aggregation suppression assay with purified proteins, EDTA chelation to assess zinc dependence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro methods (co-expression solubility, aggregation suppression, zinc chelation) in a single focused study on this specific protein, single lab\",\n      \"pmids\": [\"27253881\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1134000 (HSP70-3) is the sole mitochondrially predicted Hsp70 of P. falciparum; it is prone to self-aggregation and requires the zinc-dependent escort protein PfHep1 to maintain its solubility and prevent thermal aggregation, indicating that PfHep1 is an obligate cochaperone for PfHsp70-3 function in the mitochondria.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1134000 (HSP70-3) is the sole Hsp70 chaperone predicted to localize to the mitochondrion of Plasmodium falciparum [#0]. Purified PfHsp70-3 is intrinsically prone to self-aggregation, and this aggregation is specifically suppressed by the Hsp70-escort protein PfHep1: co-expression with PfHep1 in E. coli enhances PfHsp70-3 solubility, and purified PfHep1 prevents thermally induced aggregation of PfHsp70-3 but not of unrelated substrates such as malate dehydrogenase or citrate synthase, establishing substrate specificity [#0]. PfHep1 function depends on zinc, as EDTA chelation abolishes its ability to keep PfHsp70-3 soluble, indicating that a zinc-dependent escort chaperone is required to maintain the folding-competent, non-aggregated state of PfHsp70-3 [#0]. Beyond this escort relationship, no substrate specificity, ATPase activity, cochaperone network, or in vivo mitochondrial function of PF3D7_1134000 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"It was unknown how the aggregation-prone, mitochondrially predicted Plasmodium Hsp70 is maintained in a soluble state; this work showed that the escort protein PfHep1 specifically and zinc-dependently prevents PfHsp70-3 self-aggregation, establishing PfHep1 as an obligate cochaperone for PfHsp70-3 solubility.\",\n      \"evidence\": \"Co-expression solubility assay in E. coli plus in vitro thermal aggregation suppression with purified proteins and EDTA zinc chelation\",\n      \"pmids\": [\"27253881\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro methods in a single focused study, single lab\",\n      \"gaps\": [\n        \"The in vivo mitochondrial localization and physiological function of PfHsp70-3 in the parasite were not tested\",\n        \"No client/substrate proteins of PfHsp70-3 or its ATPase/refolding activity were characterized\",\n        \"The stoichiometry and structural basis of the PfHsp70-3–PfHep1 interaction were not resolved\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PfHsp70-3 acts as a functional folding chaperone in the parasite mitochondrion, what its substrates and nucleotide-exchange/J-domain cochaperones are, and whether the PfHep1 dependence is essential in vivo remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vivo genetic or localization data for PF3D7_1134000 in the corpus\",\n        \"No identified physiological substrates or partner chaperones beyond PfHep1\",\n        \"No structural model of PfHsp70-3 or the escort complex\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfHep1 (Hsp70-escort protein; zinc-dependent, suppresses PfHsp70-3 aggregation) [#0]\"\n    ],\n    \"other_free_text\": [\n      \"PfHsp70-3 is the sole Hsp70 predicted to localize to the P. falciparum mitochondrion [#0]\",\n      \"PfHsp70-3 is intrinsically prone to self-aggregation in vitro [#0]\",\n      \"PfHep1-mediated protection of PfHsp70-3 is zinc-dependent and abolished by EDTA [#0]\",\n      \"PfHep1 substrate specificity demonstrated: it suppresses PfHsp70-3 but not malate dehydrogenase or citrate synthase aggregation [#0]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1134000","name":null,"product":"heat shock protein 70","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0914400","name":null,"product":"heat shock protein 70, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0932200","name":null,"product":"heat shock protein 70, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"UIS24","evaluation":null}