{"gene":"PF3D7_0306200","run_date":"2026-09-07T10:55:51","timeline":{"discoveries":[{"year":2011,"finding":"P. falciparum AHA1 (PfAha1) was shown to physically interact with PfHsp90 in vivo by split-ubiquitin assay and confirmed in vitro by GST pull-down. The interaction was dependent on MgCl2 and ATP, was disrupted by high salt (indicating a polar interaction), and was competed by co-chaperone Pfp23 under the same conditions. Site-directed mutagenesis guided by bio-computational modelling identified the polar residue N108 in PfAha1 as essential for PfHsp90 binding. Functionally, PfAha1 stimulated the ATPase activity of PfHsp90, consistent with its role in promoting client protein activation.","method":"In vivo split-ubiquitin assay, in vitro GST pull-down under defined nucleotide/salt conditions, site-directed mutagenesis of N108, ATPase activity assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal binding assays (split-ubiquitin + GST pull-down) plus mutagenesis and ATPase stimulation assay, single lab","pmids":["22100910"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"P. falciparum AHA1 (PF3D7_0306200) is a co-chaperone that interacts with PfHsp90 in an ATP- and MgCl2-dependent, salt-sensitive (polar) manner—with residue N108 in PfAha1 essential for binding—and stimulates PfHsp90 ATPase activity, consistent with a role in promoting client protein activation within the parasite Hsp90 chaperone cycle."},"narrative":{"mechanistic_narrative":"PF3D7_0306200 (AHA1) is a co-chaperone of the Plasmodium falciparum Hsp90 chaperone cycle that physically interacts with PfHsp90 and stimulates its ATPase activity, consistent with a role in promoting client protein activation [PMID:22100910]. The interaction is ATP- and MgCl2-dependent and is disrupted by high salt, indicating a polar binding mode, and it is competed by the co-chaperone Pfp23; site-directed mutagenesis identified the polar residue N108 of PfAha1 as essential for PfHsp90 binding [PMID:22100910]. Beyond this characterization of PfHsp90 binding and ATPase stimulation [PMID:22100910], no further mechanistic detail—including client proteins, in vivo phenotype, or structural model—has been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Whether P. falciparum encodes a functional Aha1 co-chaperone capable of engaging and activating PfHsp90 was unknown; this work established a direct, nucleotide-dependent interaction and demonstrated that PfAha1 stimulates PfHsp90 ATPase activity, defining its role in the parasite chaperone cycle.","evidence":"In vivo split-ubiquitin assay and in vitro GST pull-down under defined ATP/MgCl2/salt conditions, N108 site-directed mutagenesis, and ATPase activity assay","pmids":["22100910"],"confidence":"Medium","gaps":["Findings derive from a single lab without independent replication","No client proteins of the PfHsp90–PfAha1 module identified","No in vivo parasite phenotype or essentiality data for PF3D7_0306200"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How PfAha1 activity is integrated with other co-chaperones during client maturation, and whether it is required for parasite viability or drug response, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the PfHsp90–PfAha1 complex","Functional interplay with Pfp23 beyond competition for binding is uncharacterized","No genetic knockout/knockdown data in the parasite"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFHSP90","PFP23"],"other_free_text":["Interaction with PfHsp90 is ATP- and MgCl2-dependent and salt-sensitive (polar interaction) [#0]","Residue N108 in PfAha1 is essential for PfHsp90 binding [#0]","PfAha1 stimulates PfHsp90 ATPase activity 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Royal Society of South Africa","url":"https://pubmed.ncbi.nlm.nih.gov/41836916","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Hsp90","PfHsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41465491","id":"PMC_41465491","title":"Plasmodium knowlesi Heat Shock Protein 90s: In Silico Analysis Reveals Unique Druggable Structural Features.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41465491","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Hsp90","PkHsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40907219","id":"PMC_40907219","title":"Investigation of a cryptic ligand binding site on Plasmodium falciparum Hsp90.","date":"2025","source":"Bioorganic & medicinal 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chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/38518861","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfHsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38252299","id":"PMC_38252299","title":"Ursolic acid acetate and iso-mukaadial acetate bind to Plasmodium falciparum Hsp90, abrogating its chaperone function in vitro.","date":"2024","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38252299","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Hsp90","PfHsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39585817","id":"PMC_39585817","title":"Auto QSAR-based active learning docking for hit identification of potential inhibitors of Plasmodium falciparum Hsp90 as antimalarial agents.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/39585817","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Hsp90","PfHsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39710055","id":"PMC_39710055","title":"Study of the naturally occurring lignan brachangobinan A as antiplasmodial agent: Synthesis, biological evaluation, and in silico prediction.","date":"2024","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/39710055","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Hsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38131664","id":"PMC_38131664","title":"Plasmodium female gamete surface HSP90 is a key determinant for fertilization.","date":"2023","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/38131664","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["Hsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36121150","id":"PMC_36121150","title":"Heat Shock Protein 90 Regulates the Activity of Histone Deacetylase Sir2 in Plasmodium falciparum.","date":"2022","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/36121150","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfHsp90"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":39167,"output_tokens":905,"usd":0.065538,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5044,"output_tokens":1278,"usd":0.028585,"stage2_stop_reason":"end_turn"},"total_usd":0.094123,"stage1_batch_id":"msgbatch_01DbiymDmubkPpYvdbAu5a7V","stage2_batch_id":"msgbatch_012TbrWvMRH129T7PQ4SmvrJ","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers that specifically discuss PF3D7_0306200 (AHA1/PfAha1), the activator of Hsp90 ATPase in P. falciparum. Most papers are about PfHsp90 itself or other co-chaperones. The key paper directly about PfAha1 is PMID:22100910.\n\nPaper [47] (PMID:22020785) mentions \"heat shock protein 90 activators PFC0360w and PFC0270w from Plasmodium falciparum\" as CASP9 targets - these are structural targets. PFC0360w and PFC0270w are gene IDs from the old annotation. PF3D7_0306200 was previously PFC0270w (one of the two Aha1-like proteins). This paper provided structures but the abstract doesn't detail functional findings about PfAha1 specifically.\n\nPaper [2] (PMID:20837488) mentions \"Aha1 and p23 binding domain\" in the context of PfHsp90 acetylation, but this is about PfHsp90, not PfAha1.\n\nPaper [46] (PMID:35892329) and [48] (PMID:24560171) mention PfAha1 as one of the characterized co-chaperones that interacts with PfHsp90, but the mechanistic detail comes from PMID:22100910.\n\nThe only paper with direct experimental findings about PfAha1 (PF3D7_0306200) itself is PMID:22100910.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"P. falciparum AHA1 (PfAha1) was shown to physically interact with PfHsp90 in vivo by split-ubiquitin assay and confirmed in vitro by GST pull-down. The interaction was dependent on MgCl2 and ATP, was disrupted by high salt (indicating a polar interaction), and was competed by co-chaperone Pfp23 under the same conditions. Site-directed mutagenesis guided by bio-computational modelling identified the polar residue N108 in PfAha1 as essential for PfHsp90 binding. Functionally, PfAha1 stimulated the ATPase activity of PfHsp90, consistent with its role in promoting client protein activation.\",\n      \"method\": \"In vivo split-ubiquitin assay, in vitro GST pull-down under defined nucleotide/salt conditions, site-directed mutagenesis of N108, ATPase activity assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal binding assays (split-ubiquitin + GST pull-down) plus mutagenesis and ATPase stimulation assay, single lab\",\n      \"pmids\": [\"22100910\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"P. falciparum AHA1 (PF3D7_0306200) is a co-chaperone that interacts with PfHsp90 in an ATP- and MgCl2-dependent, salt-sensitive (polar) manner—with residue N108 in PfAha1 essential for binding—and stimulates PfHsp90 ATPase activity, consistent with a role in promoting client protein activation within the parasite Hsp90 chaperone cycle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0306200 (AHA1) is a co-chaperone of the Plasmodium falciparum Hsp90 chaperone cycle that physically interacts with PfHsp90 and stimulates its ATPase activity, consistent with a role in promoting client protein activation [#0]. The interaction is ATP- and MgCl2-dependent and is disrupted by high salt, indicating a polar binding mode, and it is competed by the co-chaperone Pfp23; site-directed mutagenesis identified the polar residue N108 of PfAha1 as essential for PfHsp90 binding [#0]. Beyond this characterization of PfHsp90 binding and ATPase stimulation [#0], no further mechanistic detail\\u2014including client proteins, in vivo phenotype, or structural model\\u2014has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether P. falciparum encodes a functional Aha1 co-chaperone capable of engaging and activating PfHsp90 was unknown; this work established a direct, nucleotide-dependent interaction and demonstrated that PfAha1 stimulates PfHsp90 ATPase activity, defining its role in the parasite chaperone cycle.\",\n      \"evidence\": \"In vivo split-ubiquitin assay and in vitro GST pull-down under defined ATP/MgCl2/salt conditions, N108 site-directed mutagenesis, and ATPase activity assay\",\n      \"pmids\": [\n        \"22100910\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings derive from a single lab without independent replication\",\n        \"No client proteins of the PfHsp90\\u2013PfAha1 module identified\",\n        \"No in vivo parasite phenotype or essentiality data for PF3D7_0306200\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PfAha1 activity is integrated with other co-chaperones during client maturation, and whether it is required for parasite viability or drug response, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of the PfHsp90\\u2013PfAha1 complex\",\n        \"Functional interplay with Pfp23 beyond competition for binding is uncharacterized\",\n        \"No genetic knockout/knockdown data in the parasite\"\n      ],\n      \"attribution\": [\n        {\n          \"species\": \"Plasmodium falciparum\",\n          \"strain\": \"\"\n        }\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0001671\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      },\n      {\n        \"term_id\": \"GO:0051087\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0006457\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PfHsp90\",\n      \"Pfp23\"\n    ],\n    \"other_free_text\": [\n      \"Interaction with PfHsp90 is ATP- and MgCl2-dependent and salt-sensitive (polar interaction) [#0]\",\n      \"Residue N108 in PfAha1 is essential for PfHsp90 binding [#0]\",\n      \"PfAha1 stimulates PfHsp90 ATPase activity [#0]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0306200","name":null,"product":"activator of Hsp90 ATPase","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_0404600","name":null,"product":"activator of Hsp90 ATPase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0836500","name":null,"product":"activator of Hsp90 ATPase, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"AHA1","evaluation":null}