{"gene":"PF3D7_0529100","run_date":"2026-09-11T10:06:41","timeline":{"discoveries":[{"year":2013,"finding":"ATrx2 (PF3D7_0529100) is a genuine member of the Plasmodium Translocon of Exported Proteins (PTEX) complex, validated by genetic tagging and co-purification experiments. Deletion of ATrx2 in P. berghei was achievable (unlike other PTEX core components), and knockout parasites displayed reduced growth rates in vivo and in vitro and reduced capacity to cause severe disease in a cerebral malaria model, indicating ATrx2 is not essential for parasite survival but optimizes PTEX activity.","method":"Genetic tagging, knockout parasite generation, in vivo and in vitro growth assays, cerebral malaria model","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic deletion with defined phenotypic readouts (growth rate, disease severity) in two experimental systems (in vivo and in vitro), validating PTEX membership with functional consequences","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"ATrx2 (PF3D7_0529100) is expressed not only in asexual blood stages but also in early gametocytes, mosquito stages, and liver stages, consistent with protein export occurring across multiple life-cycle stages.","method":"Expression analysis of tagged PTEX components across life-cycle stages","journal":"Molecular microbiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct detection of tagged protein at multiple life-cycle stages in a single study, single lab","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2017,"finding":"ATrx2 (PF3D7_0529100, referred to as Thioredoxin 2 in this study) is a poor substrate for thioredoxin reductase and lacks access to thioredoxin reductase in its subcellular compartment; however, the glutathione system (glutathione/glutaredoxin pathway) can reduce ATrx2, demonstrating functional cross-talk between the glutathione and thioredoxin antioxidant systems in P. falciparum.","method":"In vitro biochemical reduction assays measuring cross-system reduction of thioredoxins by glutathione system components","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assay establishing enzymatic activity (reduction) of ATrx2 by the glutathione system, but from a single lab with no mutagenesis or structural validation","pmids":["28479253"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"ATrx2 (PF3D7_0529100) is a non-essential but functionally important member of the PTEX protein export complex expressed across multiple P. falciparum life-cycle stages; its deletion reduces parasite growth and virulence, suggesting it optimizes PTEX activity, and biochemically it functions as a thioredoxin-like protein that is a poor substrate for thioredoxin reductase but can be reduced by the glutathione system, linking the two antioxidant networks in the parasite."},"narrative":{"mechanistic_narrative":"ATrx2 (PF3D7_0529100) is a thioredoxin-like component of the Plasmodium Translocon of Exported Proteins (PTEX), the machinery that mediates protein export across multiple life-cycle stages [PMID:23869529]. Unlike other PTEX core subunits, ATrx2 can be deleted; in P. berghei, knockout parasites remain viable but exhibit reduced growth in vivo and in vitro and reduced capacity to cause severe disease in a cerebral malaria model, indicating that ATrx2 is not essential but optimizes PTEX activity [PMID:23869529]. Consistent with export occurring throughout the parasite life cycle, tagged ATrx2 is detected in asexual blood stages, early gametocytes, mosquito stages, and liver stages [PMID:23869529]. Biochemically, ATrx2 is a poor substrate for thioredoxin reductase and lacks access to it in its subcellular compartment, but it can be reduced by the glutathione/glutaredoxin pathway, positioning it at a point of cross-talk between the parasite's glutathione and thioredoxin antioxidant systems [PMID:28479253]. Beyond these findings, the redox role of ATrx2 within PTEX and its physiological substrates have not been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Establishing whether ATrx2 is a bona fide PTEX subunit and whether it is required for parasite survival was needed to define its role in protein export; genetic tagging placed it in the complex and knockout revealed it is dispensable but growth- and virulence-promoting.","evidence":"Genetic tagging and co-purification plus knockout with in vivo/in vitro growth assays and a cerebral malaria model","pmids":["23869529"],"confidence":"High","gaps":["The molecular contribution of ATrx2 to translocation (e.g. a redox step) was not defined","The reduced-growth phenotype was shown in P. berghei; equivalent knockout phenotype in P. falciparum was not established","No substrates or interaction interface within PTEX mapped"],"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Whether ATrx2-dependent export operates outside asexual blood stages was open; detection of tagged ATrx2 across gametocyte, mosquito, and liver stages indicated PTEX-associated activity spans the life cycle.","evidence":"Expression analysis of tagged PTEX components across life-cycle stages","pmids":["23869529"],"confidence":"Medium","gaps":["Expression detection does not establish functional export requirement at each stage","Single-study, single-lab detection without independent confirmation"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"How ATrx2, a thioredoxin-like protein, is kept in a reduced state was unknown; in vitro assays showed it is a poor thioredoxin reductase substrate but is reducible by the glutathione system, revealing cross-talk between the two antioxidant networks.","evidence":"In vitro biochemical reduction assays measuring cross-system reduction by glutathione pathway components","pmids":["28479253"],"confidence":"Medium","gaps":["In vitro assay from a single lab without mutagenesis or structural validation","The physiological redox substrates of ATrx2 and the link to PTEX function were not established","Subcellular compartment claim inferred from access data rather than direct localization"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"It remains unknown what redox reaction, if any, ATrx2 performs during protein translocation and which exported substrates or PTEX partners depend on its thioredoxin-like activity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mechanistic link between ATrx2 redox activity and PTEX translocation demonstrated","No structural model of ATrx2 or its complex interface","No identified physiological reducing substrates"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PTEX (Plasmodium Translocon of Exported Proteins)"],"partners":[],"other_free_text":["Non-essential PTEX component whose deletion reduces parasite growth and virulence in a P. berghei cerebral malaria model [#0]","Expressed across asexual blood, early gametocyte, mosquito, and liver stages [#1]","Thioredoxin-like protein that is a poor substrate for thioredoxin reductase but reducible by the glutathione/glutaredoxin system, linking the two antioxidant networks [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"23869529","id":"PMC_23869529","title":"The Plasmodium translocon of exported proteins (PTEX) component thioredoxin-2 is important for maintaining normal blood-stage growth.","date":"2013","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23869529","citation_count":72,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin-like protein"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30514877","id":"PMC_30514877","title":"The origins of malaria artemisinin resistance defined by a genetic and transcriptomic background.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30514877","citation_count":44,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin-like protein"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28479253","id":"PMC_28479253","title":"Glutathione and thioredoxin systems of the malaria parasite Plasmodium falciparum: Partners in crime?","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28479253","citation_count":16,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin-like protein"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4050,"output_tokens":990,"usd":0.0135,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5740,"output_tokens":1943,"usd":0.038637,"stage2_stop_reason":"end_turn"},"total_usd":0.052137,"stage1_batch_id":"msgbatch_01DbiymDmubkPpYvdbAu5a7V","stage2_batch_id":"msgbatch_012TbrWvMRH129T7PQ4SmvrJ","note":"batch pricing = 50% of standard","patch_2026_09_11":["species attribution corrected after review"]},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"ATrx2 (PF3D7_0529100) is a genuine member of the Plasmodium Translocon of Exported Proteins (PTEX) complex, validated by genetic tagging and co-purification experiments. Deletion of ATrx2 in P. berghei was achievable (unlike other PTEX core components), and knockout parasites displayed reduced growth rates in vivo and in vitro and reduced capacity to cause severe disease in a cerebral malaria model, indicating ATrx2 is not essential for parasite survival but optimizes PTEX activity.\",\n      \"method\": \"Genetic tagging, knockout parasite generation, in vivo and in vitro growth assays, cerebral malaria model\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deletion with defined phenotypic readouts (growth rate, disease severity) in two experimental systems (in vivo and in vitro), validating PTEX membership with functional consequences\",\n      \"pmids\": [\"23869529\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATrx2 (PF3D7_0529100) is expressed not only in asexual blood stages but also in early gametocytes, mosquito stages, and liver stages, consistent with protein export occurring across multiple life-cycle stages.\",\n      \"method\": \"Expression analysis of tagged PTEX components across life-cycle stages\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct detection of tagged protein at multiple life-cycle stages in a single study, single lab\",\n      \"pmids\": [\"23869529\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATrx2 (PF3D7_0529100, referred to as Thioredoxin 2 in this study) is a poor substrate for thioredoxin reductase and lacks access to thioredoxin reductase in its subcellular compartment; however, the glutathione system (glutathione/glutaredoxin pathway) can reduce ATrx2, demonstrating functional cross-talk between the glutathione and thioredoxin antioxidant systems in P. falciparum.\",\n      \"method\": \"In vitro biochemical reduction assays measuring cross-system reduction of thioredoxins by glutathione system components\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assay establishing enzymatic activity (reduction) of ATrx2 by the glutathione system, but from a single lab with no mutagenesis or structural validation\",\n      \"pmids\": [\"28479253\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"ATrx2 (PF3D7_0529100) is a non-essential but functionally important member of the PTEX protein export complex expressed across multiple P. falciparum life-cycle stages; its deletion reduces parasite growth and virulence, suggesting it optimizes PTEX activity, and biochemically it functions as a thioredoxin-like protein that is a poor substrate for thioredoxin reductase but can be reduced by the glutathione system, linking the two antioxidant networks in the parasite.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATrx2 (PF3D7_0529100) is a thioredoxin-like component of the Plasmodium Translocon of Exported Proteins (PTEX), the machinery that mediates protein export across multiple life-cycle stages [#0, #1]. Unlike other PTEX core subunits, ATrx2 can be deleted; in P. berghei, knockout parasites remain viable but exhibit reduced growth in vivo and in vitro and reduced capacity to cause severe disease in a cerebral malaria model, indicating that ATrx2 is not essential but optimizes PTEX activity [#0]. Consistent with export occurring throughout the parasite life cycle, tagged ATrx2 is detected in asexual blood stages, early gametocytes, mosquito stages, and liver stages [#1]. Biochemically, ATrx2 is a poor substrate for thioredoxin reductase and lacks access to it in its subcellular compartment, but it can be reduced by the glutathione/glutaredoxin pathway, positioning it at a point of cross-talk between the parasite's glutathione and thioredoxin antioxidant systems [#2]. Beyond these findings, the redox role of ATrx2 within PTEX and its physiological substrates have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing whether ATrx2 is a bona fide PTEX subunit and whether it is required for parasite survival was needed to define its role in protein export; genetic tagging placed it in the complex and knockout revealed it is dispensable but growth- and virulence-promoting.\",\n      \"evidence\": \"Genetic tagging and co-purification plus knockout with in vivo/in vitro growth assays and a cerebral malaria model\",\n      \"pmids\": [\"23869529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The molecular contribution of ATrx2 to translocation (e.g. a redox step) was not defined\",\n        \"The reduced-growth phenotype was shown in P. berghei; equivalent knockout phenotype in P. falciparum was not established\",\n        \"No substrates or interaction interface within PTEX mapped\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether ATrx2-dependent export operates outside asexual blood stages was open; detection of tagged ATrx2 across gametocyte, mosquito, and liver stages indicated PTEX-associated activity spans the life cycle.\",\n      \"evidence\": \"Expression analysis of tagged PTEX components across life-cycle stages\",\n      \"pmids\": [\"23869529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Expression detection does not establish functional export requirement at each stage\",\n        \"Single-study, single-lab detection without independent confirmation\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"How ATrx2, a thioredoxin-like protein, is kept in a reduced state was unknown; in vitro assays showed it is a poor thioredoxin reductase substrate but is reducible by the glutathione system, revealing cross-talk between the two antioxidant networks.\",\n      \"evidence\": \"In vitro biochemical reduction assays measuring cross-system reduction by glutathione pathway components\",\n      \"pmids\": [\"28479253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vitro assay from a single lab without mutagenesis or structural validation\",\n        \"The physiological redox substrates of ATrx2 and the link to PTEX function were not established\",\n        \"Subcellular compartment claim inferred from access data rather than direct localization\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what redox reaction, if any, ATrx2 performs during protein translocation and which exported substrates or PTEX partners depend on its thioredoxin-like activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mechanistic link between ATrx2 redox activity and PTEX translocation demonstrated\",\n        \"No structural model of ATrx2 or its complex interface\",\n        \"No identified physiological reducing substrates\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0015035\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006612\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"PTEX (Plasmodium Translocon of Exported Proteins)\"],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Non-essential PTEX component whose deletion reduces parasite growth and virulence in a P. berghei cerebral malaria model [#0]\",\n      \"Expressed across asexual blood, early gametocyte, mosquito, and liver stages [#1]\",\n      \"Thioredoxin-like protein that is a poor substrate for thioredoxin reductase but reducible by the glutathione/glutaredoxin system, linking the two antioxidant networks [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0529100","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1243700","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1003600","name":null,"product":"thioredoxin-like protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ATrx2","evaluation":null}