{"gene":"PF3D7_1318600","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2009,"finding":"TRX2 (PF3D7_1318600) was identified as a component of the PTEX (Plasmodium translocon of exported proteins) complex, which is located in the parasitophorous vacuole membrane and is ATP-powered. TRX2 was co-purified with HSP101, PTEX150, EXP2, and PTEX88 as part of this complex.","method":"Co-immunoprecipitation / complex purification followed by mass spectrometry identification","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP/complex purification identifying TRX2 as a PTEX component, confirmed by multiple labs subsequently","pmids":["19536257"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"TRX2 (PF3D7_1318600) was validated as a genuine PTEX component by genetic tagging and localization experiments. TRX2 knockout in P. berghei was achievable and resulted in reduced blood-stage growth rates both in vivo and in vitro, and reduced capacity to cause severe disease in a cerebral malaria model, indicating TRX2 is important but not essential for parasite survival.","method":"Genetic knockout in P. berghei, in vivo and in vitro growth assays, cerebral malaria mouse model","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular and in vivo phenotype, replicated across two labs (Matthews et al. and Matz et al.)","pmids":["23869529"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"finding":"TRX2 (PF3D7_1318600) knockout in P. berghei showed reduced multiplication rate and was out-competed by wild-type parasites in a competition assay. Endogenous tagging revealed that TRX2::tag resides in distinct punctate organelles of unknown identity, distinct from the diffuse intraparasitic pattern of PTEX88.","method":"Genetic knockout, flow cytometry-assisted intravital competition assay, endogenous protein tagging and fluorescence microscopy","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with defined phenotype and direct localization experiment, independently replicated finding of TRX2 dispensability","pmids":["24076174"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2015,"finding":"TRX2 (PF3D7_1318600) knockout in P. berghei showed that TRX2-deficient parasites remain virulent but display reduced efficient sequestration to pulmonary, adipose, and brain tissue vasculature. Unlike PTEX88 knockout, general protein export was unaffected in TRX2-deficient parasites, indicating TRX2 influences sequestration but is not required for general protein export.","method":"Genetic knockout in P. berghei, in vivo sequestration assays, tissue localization studies","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined in vivo phenotypic readouts and negative result on protein export, multiple orthogonal assays","pmids":["25820521"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":2011,"finding":"PfTRX2 (PF3D7_1318600) localizes to the parasitophorous vacuolar membrane (PVM) of P. falciparum, as determined by confocal microscopy, consistent with its role as a PTEX component at the PVM.","method":"Confocal microscopy of GFP/tagged fusion proteins in P. falciparum","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct confocal localization experiment, single lab, consistent with biochemical complex data from another lab","pmids":["22355694"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"finding":"PfTRX2 (PF3D7_1318600) adopts a canonical thioredoxin fold with significant structural differences in its N-terminus, as determined by X-ray crystallography. Small molecule inhibitors targeting unique structural features of PfTrx-2 were identified by library screening.","method":"X-ray crystallography, small molecule library screening","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure solved, but functional validation of structural differences and inhibitor effects was limited in the abstract","pmids":["22355694"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_1318600 (TRX2/thioredoxin-2) is a component of the PTEX protein export translocon complex embedded in the parasitophorous vacuole membrane; it adopts a canonical thioredoxin fold and localizes to the PVM/distinct punctate organelles, and while its deletion reduces blood-stage growth and in vivo sequestration in rodent malaria models, it is not essential for parasite survival or general protein export through PTEX."},"narrative":{"mechanistic_narrative":"PF3D7_1318600 (TRX2/thioredoxin-2) is a component of the ATP-powered PTEX (Plasmodium translocon of exported proteins) complex at the parasitophorous vacuole membrane, where it was co-purified with HSP101, PTEX150, EXP2, and PTEX88 [PMID:19536257]. It localizes to the parasitophorous vacuolar membrane in P. falciparum [PMID:22355694] and, when endogenously tagged in P. berghei, additionally resides in distinct punctate organelles of unknown identity, unlike the diffuse pattern of PTEX88 [PMID:24076174]. Structurally it adopts a canonical thioredoxin fold with distinctive N-terminal features that have been exploited to identify small-molecule inhibitors [PMID:22355694]. Functionally, TRX2 is important but not essential: knockout in P. berghei reduces blood-stage multiplication and competitive fitness and lowers the capacity to cause severe cerebral disease [PMID:23869529, PMID:24076174], and TRX2-deficient parasites remain virulent but show reduced sequestration to pulmonary, adipose, and brain vasculature, while general protein export through PTEX is unaffected—distinguishing it from PTEX88 [PMID:25820521]. Beyond these findings, the biochemical redox activity and substrate(s) of TRX2 within PTEX have not been characterized in the available corpus.","teleology":[{"year":2009,"claim":"Establishing which proteins constitute the parasite's protein-export machinery was the first step; identifying TRX2 as a co-purifying PTEX subunit placed a thioredoxin at the parasitophorous vacuole membrane translocon.","evidence":"Co-immunoprecipitation/complex purification and mass spectrometry of the PTEX complex in P. falciparum","pmids":["19536257"],"confidence":"Medium","gaps":["Does not establish a redox or enzymatic role for TRX2 within the complex","Single Co-IP/complex purification; stoichiometry and direct binding partners of TRX2 not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2011,"claim":"Whether TRX2 has a thioredoxin architecture and a defined subcellular position was unknown; crystallography revealed a canonical thioredoxin fold with unique N-terminal features, and confocal microscopy placed the protein at the PVM, consistent with its PTEX membership.","evidence":"X-ray crystallography, small-molecule library screening, and confocal microscopy of tagged fusions in P. falciparum","pmids":["22355694"],"confidence":"Medium","gaps":["Functional consequences of the N-terminal structural differences not demonstrated","Inhibitor effects on parasite/TRX2 function not validated in the finding","Catalytic redox partners/substrates unidentified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Whether TRX2 is required for parasite survival was resolved by genetic ablation: knockout in P. berghei was viable but reduced blood-stage growth, competitive fitness, and severe-disease capacity, defining TRX2 as important but non-essential.","evidence":"Genetic knockout, in vivo/in vitro growth assays, intravital competition assay, endogenous tagging, and cerebral malaria mouse model in P. berghei (validated as a genuine PTEX component in P. falciparum)","pmids":["23869529","24076174"],"confidence":"High","gaps":["Mechanism linking TRX2 loss to reduced multiplication not defined","Identity of the distinct punctate TRX2-positive organelles unknown"],"attribution":[{"species":"Plasmodium berghei","strain":""},{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"The specific role of TRX2 relative to other PTEX subunits was clarified: its loss impairs tissue sequestration without disrupting general protein export, distinguishing TRX2 from PTEX88 and separating its function from the core translocation activity of PTEX.","evidence":"Genetic knockout in P. berghei with in vivo sequestration and tissue localization assays and a protein-export readout","pmids":["25820521"],"confidence":"High","gaps":["Molecular basis by which TRX2 influences sequestration is unresolved","Whether the sequestration phenotype reflects redox activity or a structural role within PTEX is unknown"],"attribution":[{"species":"Plasmodium berghei","strain":""}]},{"year":null,"claim":"The biochemical redox function and physiological substrate(s) of TRX2 within PTEX, and the identity of the punctate organelles it occupies, remain unestablished.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No demonstrated thioredoxin substrate or redox activity within the complex","Identity of TRX2-positive punctate organelles unknown","Mechanistic link between TRX2 and tissue sequestration undefined"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["PTEX (Plasmodium translocon of exported proteins) — with HSP101, PTEX150, EXP2, PTEX88 [#0]"],"partners":["HSP101 [#0]","PTEX150 [#0]","EXP2 [#0]","PTEX88 [#0]"],"other_free_text":["Adopts a canonical thioredoxin fold with distinctive N-terminal structural features [#5]","Knockout in P. berghei is viable but reduces blood-stage growth, competitive fitness, and severe-disease capacity [#1, #2]","TRX2 loss reduces tissue sequestration but does not impair general protein export, unlike PTEX88 knockout [#3]","Endogenously tagged TRX2 localizes to distinct punctate organelles of unknown identity in P. berghei [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"15037104","id":"PMC_15037104","title":"Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions.","date":"2004","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15037104","citation_count":449,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["thioredoxin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"19536257","id":"PMC_19536257","title":"A newly discovered protein export machine in malaria 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TRX2 was co-purified with HSP101, PTEX150, EXP2, and PTEX88 as part of this complex.\",\n      \"method\": \"Co-immunoprecipitation / complex purification followed by mass spectrometry identification\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP/complex purification identifying TRX2 as a PTEX component, confirmed by multiple labs subsequently\",\n      \"pmids\": [\"19536257\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRX2 (PF3D7_1318600) was validated as a genuine PTEX component by genetic tagging and localization experiments. TRX2 knockout in P. berghei was achievable and resulted in reduced blood-stage growth rates both in vivo and in vitro, and reduced capacity to cause severe disease in a cerebral malaria model, indicating TRX2 is important but not essential for parasite survival.\",\n      \"method\": \"Genetic knockout in P. berghei, in vivo and in vitro growth assays, cerebral malaria mouse model\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular and in vivo phenotype, replicated across two labs (Matthews et al. and Matz et al.)\",\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\": \"TRX2 (PF3D7_1318600) knockout in P. berghei showed reduced multiplication rate and was out-competed by wild-type parasites in a competition assay. Endogenous tagging revealed that TRX2::tag resides in distinct punctate organelles of unknown identity, distinct from the diffuse intraparasitic pattern of PTEX88.\",\n      \"method\": \"Genetic knockout, flow cytometry-assisted intravital competition assay, endogenous protein tagging and fluorescence microscopy\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with defined phenotype and direct localization experiment, independently replicated finding of TRX2 dispensability\",\n      \"pmids\": [\"24076174\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRX2 (PF3D7_1318600) knockout in P. berghei showed that TRX2-deficient parasites remain virulent but display reduced efficient sequestration to pulmonary, adipose, and brain tissue vasculature. Unlike PTEX88 knockout, general protein export was unaffected in TRX2-deficient parasites, indicating TRX2 influences sequestration but is not required for general protein export.\",\n      \"method\": \"Genetic knockout in P. berghei, in vivo sequestration assays, tissue localization studies\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined in vivo phenotypic readouts and negative result on protein export, multiple orthogonal assays\",\n      \"pmids\": [\"25820521\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PfTRX2 (PF3D7_1318600) localizes to the parasitophorous vacuolar membrane (PVM) of P. falciparum, as determined by confocal microscopy, consistent with its role as a PTEX component at the PVM.\",\n      \"method\": \"Confocal microscopy of GFP/tagged fusion proteins in P. falciparum\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct confocal localization experiment, single lab, consistent with biochemical complex data from another lab\",\n      \"pmids\": [\"22355694\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PfTRX2 (PF3D7_1318600) adopts a canonical thioredoxin fold with significant structural differences in its N-terminus, as determined by X-ray crystallography. Small molecule inhibitors targeting unique structural features of PfTrx-2 were identified by library screening.\",\n      \"method\": \"X-ray crystallography, small molecule library screening\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure solved, but functional validation of structural differences and inhibitor effects was limited in the abstract\",\n      \"pmids\": [\"22355694\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1318600 (TRX2/thioredoxin-2) is a component of the PTEX protein export translocon complex embedded in the parasitophorous vacuole membrane; it adopts a canonical thioredoxin fold and localizes to the PVM/distinct punctate organelles, and while its deletion reduces blood-stage growth and in vivo sequestration in rodent malaria models, it is not essential for parasite survival or general protein export through PTEX.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1318600 (TRX2/thioredoxin-2) is a component of the ATP-powered PTEX (Plasmodium translocon of exported proteins) complex at the parasitophorous vacuole membrane, where it was co-purified with HSP101, PTEX150, EXP2, and PTEX88 [#0]. It localizes to the parasitophorous vacuolar membrane in P. falciparum [#4] and, when endogenously tagged in P. berghei, additionally resides in distinct punctate organelles of unknown identity, unlike the diffuse pattern of PTEX88 [#2]. Structurally it adopts a canonical thioredoxin fold with distinctive N-terminal features that have been exploited to identify small-molecule inhibitors [#5]. Functionally, TRX2 is important but not essential: knockout in P. berghei reduces blood-stage multiplication and competitive fitness and lowers the capacity to cause severe cerebral disease [#1, #2], and TRX2-deficient parasites remain virulent but show reduced sequestration to pulmonary, adipose, and brain vasculature, while general protein export through PTEX is unaffected—distinguishing it from PTEX88 [#3]. Beyond these findings, the biochemical redox activity and substrate(s) of TRX2 within PTEX have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing which proteins constitute the parasite's protein-export machinery was the first step; identifying TRX2 as a co-purifying PTEX subunit placed a thioredoxin at the parasitophorous vacuole membrane translocon.\",\n      \"evidence\": \"Co-immunoprecipitation/complex purification and mass spectrometry of the PTEX complex in P. falciparum\",\n      \"pmids\": [\"19536257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish a redox or enzymatic role for TRX2 within the complex\", \"Single Co-IP/complex purification; stoichiometry and direct binding partners of TRX2 not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether TRX2 has a thioredoxin architecture and a defined subcellular position was unknown; crystallography revealed a canonical thioredoxin fold with unique N-terminal features, and confocal microscopy placed the protein at the PVM, consistent with its PTEX membership.\",\n      \"evidence\": \"X-ray crystallography, small-molecule library screening, and confocal microscopy of tagged fusions in P. falciparum\",\n      \"pmids\": [\"22355694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of the N-terminal structural differences not demonstrated\", \"Inhibitor effects on parasite/TRX2 function not validated in the finding\", \"Catalytic redox partners/substrates unidentified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether TRX2 is required for parasite survival was resolved by genetic ablation: knockout in P. berghei was viable but reduced blood-stage growth, competitive fitness, and severe-disease capacity, defining TRX2 as important but non-essential.\",\n      \"evidence\": \"Genetic knockout, in vivo/in vitro growth assays, intravital competition assay, endogenous tagging, and cerebral malaria mouse model in P. berghei (validated as a genuine PTEX component in P. falciparum)\",\n      \"pmids\": [\"23869529\", \"24076174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking TRX2 loss to reduced multiplication not defined\", \"Identity of the distinct punctate TRX2-positive organelles unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The specific role of TRX2 relative to other PTEX subunits was clarified: its loss impairs tissue sequestration without disrupting general protein export, distinguishing TRX2 from PTEX88 and separating its function from the core translocation activity of PTEX.\",\n      \"evidence\": \"Genetic knockout in P. berghei with in vivo sequestration and tissue localization assays and a protein-export readout\",\n      \"pmids\": [\"25820521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis by which TRX2 influences sequestration is unresolved\", \"Whether the sequestration phenotype reflects redox activity or a structural role within PTEX is unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical redox function and physiological substrate(s) of TRX2 within PTEX, and the identity of the punctate organelles it occupies, remain unestablished.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No demonstrated thioredoxin substrate or redox activity within the complex\", \"Identity of TRX2-positive punctate organelles unknown\", \"Mechanistic link between TRX2 and tissue sequestration undefined\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0015035\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020005\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0065002\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [\n      \"PTEX (Plasmodium translocon of exported proteins) — with HSP101, PTEX150, EXP2, PTEX88 [#0]\"\n    ],\n    \"partners\": [\n      \"HSP101 [#0]\",\n      \"PTEX150 [#0]\",\n      \"EXP2 [#0]\",\n      \"PTEX88 [#0]\"\n    ],\n    \"other_free_text\": [\n      \"Adopts a canonical thioredoxin fold with distinctive N-terminal structural features [#5]\",\n      \"Knockout in P. berghei is viable but reduces blood-stage growth, competitive fitness, and severe-disease capacity [#1, #2]\",\n      \"TRX2 loss reduces tissue sequestration but does not impair general protein export, unlike PTEX88 knockout [#3]\",\n      \"Endogenously tagged TRX2 localizes to distinct punctate organelles of unknown identity in P. berghei [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1318600","name":null,"product":"thioredoxin, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1417100","name":null,"product":"thioredoxin, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1419400","name":null,"product":"thioredoxin, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}