{"gene":"PF3D7_0202400","run_date":"2026-09-07T10:55:51","timeline":{"discoveries":[{"year":2017,"finding":"PTEF (PF3D7_0202400) relieves upstream open reading frame (uORF) repression to facilitate translation of VAR2CSA (PfEMP1-VAR2CSA); VAR2CSA protein levels in var2csa-transcribing parasites depend on the expression level of PTEF.","method":"Genetic manipulation of PTEF expression levels combined with measurement of VAR2CSA protein output in P. falciparum","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods in a single study (expression-level manipulation, proteolytic processing assay, ribosome interaction, heterologous translation system), all in a peer-reviewed journal","pmids":["28481333"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"PTEF requires proteolytic cleavage by PfCalpain to alleviate uORF repression; cleavage generates a C-terminal domain containing a sterile-alpha-motif (SAM)-like domain.","method":"In vitro and cellular proteolytic processing assays identifying PfCalpain as the protease responsible for PTEF cleavage, with domain characterization","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical identification of the processing protease and domain structure in a single rigorous study with multiple methods","pmids":["28481333"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"The C-terminal domain of PTEF (generated by PfCalpain cleavage) is permissive to cytoplasmic shuttling and directly interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence.","method":"Subcellular localization experiments (cytoplasmic shuttling assay) and ribosome interaction assay (pulldown/co-fractionation)","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization and ribosome-interaction experiments in a single rigorous multi-method study","pmids":["28481333"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"The C-terminal domain of PTEF enhances translation in a heterologous translation system, establishing it as a non-canonical translation-enhancing factor in a protozoan.","method":"Heterologous (cell-free or non-Plasmodium) translation assay with PTEF C-terminal domain","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution in a heterologous system, single lab, single paper","pmids":["28481333"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"PTEF activity regulates placental CSA binding of P. falciparum-infected erythrocytes, linking its translational regulation of VAR2CSA to a functional adhesion phenotype.","method":"Functional CSA binding assay in parasites with manipulated PTEF expression","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional assay in a single lab study; adhesion phenotype linked to PTEF expression level but single paper","pmids":["28481333"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PTEF (PF3D7_0202400) is a non-canonical translation-enhancing factor in P. falciparum that is proteolytically processed by PfCalpain to release a C-terminal SAM-like domain, which shuttles to the cytoplasm, associates with ribosomes, and relieves upstream open reading frame-mediated repression of VAR2CSA translation, thereby controlling placental CSA-binding of infected erythrocytes."},"narrative":{"mechanistic_narrative":"PTEF (PF3D7_0202400) is a non-canonical translation-enhancing factor in Plasmodium falciparum that couples proteolytic processing to the translational control of the placental cytoadherence ligand VAR2CSA [PMID:28481333]. PTEF is cleaved by PfCalpain, a step that liberates a C-terminal domain containing a sterile-alpha-motif (SAM)-like fold [PMID:28481333]. This released C-terminal domain shuttles to the cytoplasm and associates directly with ribosomes, where it relieves upstream open reading frame (uORF)-mediated repression of the var2csa coding sequence, so that VAR2CSA protein output in var2csa-transcribing parasites scales with PTEF expression level [PMID:28481333]. The isolated C-terminal domain enhances translation in a heterologous system, establishing PTEF's intrinsic translation-enhancing activity [PMID:28481333]. Through this control of VAR2CSA translation, PTEF activity governs the CSA-binding adhesion phenotype of infected erythrocytes [PMID:28481333]. Beyond this processing-and-derepression mechanism defined in a single study, no further mechanistic detail on PTEF has been characterized in the available corpus.","teleology":[{"year":2017,"claim":"Established that VAR2CSA translation is not solely transcriptionally controlled but depends on a dedicated factor that overcomes uORF repression, identifying PTEF as that factor.","evidence":"Genetic manipulation of PTEF expression with measurement of VAR2CSA protein output in P. falciparum","pmids":["28481333"],"confidence":"High","gaps":["Does not define how PTEF specifically recognizes the var2csa uORF versus other uORF-containing transcripts","Quantitative relationship between PTEF dose and derepression not fully mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Explained how PTEF is activated, showing that its function requires PfCalpain cleavage to release a C-terminal SAM-like domain rather than acting as a full-length protein.","evidence":"In vitro and cellular proteolytic processing assays identifying PfCalpain, with domain characterization, in P. falciparum","pmids":["28481333"],"confidence":"High","gaps":["Trigger and timing of PfCalpain cleavage during the cell cycle not established","Fate and function of the non-C-terminal portion of PTEF unknown"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Localized the active fragment and its target, showing the cleaved C-terminal domain shuttles to the cytoplasm and binds ribosomes to derepress var2csa translation.","evidence":"Subcellular localization (cytoplasmic shuttling) and ribosome interaction/co-fractionation assays in P. falciparum","pmids":["28481333"],"confidence":"High","gaps":["Ribosomal contact site and stoichiometry not resolved","Mechanism by which ribosome association overrides uORF stalling not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Demonstrated the C-terminal domain has intrinsic translation-enhancing activity independent of the parasite context.","evidence":"Heterologous cell-free/non-Plasmodium translation assay with the PTEF C-terminal domain","pmids":["28481333"],"confidence":"Medium","gaps":["Heterologous system may not recapitulate Plasmodium-specific cofactor requirements","Not reconstituted with defined ribosomal components","Single lab, single study"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Connected PTEF's translational role to a disease-relevant phenotype, showing PTEF activity controls CSA-binding of infected erythrocytes.","evidence":"Functional CSA binding assay in parasites with manipulated PTEF expression","pmids":["28481333"],"confidence":"Medium","gaps":["Contribution of PTEF to adhesion phenotypes mediated by other PfEMP1 variants not tested","In vivo relevance to placental sequestration not addressed","Single paper"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How PTEF selectively targets particular uORF-containing mRNAs, the structural basis of its ribosome interaction, and its broader role in the parasite translatome remain unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of PTEF or its ribosome complex","Transcript selectivity determinants unknown","Whether PTEF regulates targets beyond var2csa uncharacterized"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["PFCALPAIN (PROTEASE THAT CLEAVES PTEF)","RIBOSOME (BOUND BY THE PTEF C-TERMINAL DOMAIN)","VAR2CSA MRNA (TRANSLATIONAL TARGET)"],"other_free_text":["PTEF is proteolytically processed by PfCalpain to release a C-terminal SAM-like domain that constitutes the active translation-enhancing fragment [#1].","PTEF controls VAR2CSA protein output by relieving uORF-mediated translational repression, linking it to the CSA-binding placental adhesion phenotype of infected erythrocytes [#0, #4].","All current knowledge of PTEF derives from a single 2017 study; no independent replication or structural data are present in the corpus."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"17196675","id":"PMC_17196675","title":"Comparative transcriptomal analysis of isogenic Plasmodium falciparum clones of distinct antigenic and adhesive phenotypes.","date":"2006","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/17196675","citation_count":35,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PFB0115w"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28481333","id":"PMC_28481333","title":"Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor.","date":"2017","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28481333","citation_count":29,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PTEF","translation-enhancing factor"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23901091","id":"PMC_23901091","title":"Differential protein expression profiles between Plasmodium falciparum parasites isolated from subjects presenting with pregnancy-associated malaria and uncomplicated malaria in Benin.","date":"2013","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23901091","citation_count":17,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PFB0115w"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29121643","id":"PMC_29121643","title":"PFI1785w: A highly conserved protein associated with pregnancy associated malaria.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29121643","citation_count":5,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PFB0115w"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4781,"output_tokens":1221,"usd":0.016329,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6099,"output_tokens":2426,"usd":0.045573,"stage2_stop_reason":"end_turn"},"total_usd":0.061902,"stage1_batch_id":"msgbatch_01DbiymDmubkPpYvdbAu5a7V","stage2_batch_id":"msgbatch_012TbrWvMRH129T7PQ4SmvrJ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"PTEF (PF3D7_0202400) relieves upstream open reading frame (uORF) repression to facilitate translation of VAR2CSA (PfEMP1-VAR2CSA); VAR2CSA protein levels in var2csa-transcribing parasites depend on the expression level of PTEF.\",\n      \"method\": \"Genetic manipulation of PTEF expression levels combined with measurement of VAR2CSA protein output in P. falciparum\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods in a single study (expression-level manipulation, proteolytic processing assay, ribosome interaction, heterologous translation system), all in a peer-reviewed journal\",\n      \"pmids\": [\"28481333\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTEF requires proteolytic cleavage by PfCalpain to alleviate uORF repression; cleavage generates a C-terminal domain containing a sterile-alpha-motif (SAM)-like domain.\",\n      \"method\": \"In vitro and cellular proteolytic processing assays identifying PfCalpain as the protease responsible for PTEF cleavage, with domain characterization\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical identification of the processing protease and domain structure in a single rigorous study with multiple methods\",\n      \"pmids\": [\"28481333\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C-terminal domain of PTEF (generated by PfCalpain cleavage) is permissive to cytoplasmic shuttling and directly interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence.\",\n      \"method\": \"Subcellular localization experiments (cytoplasmic shuttling assay) and ribosome interaction assay (pulldown/co-fractionation)\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and ribosome-interaction experiments in a single rigorous multi-method study\",\n      \"pmids\": [\"28481333\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C-terminal domain of PTEF enhances translation in a heterologous translation system, establishing it as a non-canonical translation-enhancing factor in a protozoan.\",\n      \"method\": \"Heterologous (cell-free or non-Plasmodium) translation assay with PTEF C-terminal domain\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution in a heterologous system, single lab, single paper\",\n      \"pmids\": [\"28481333\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTEF activity regulates placental CSA binding of P. falciparum-infected erythrocytes, linking its translational regulation of VAR2CSA to a functional adhesion phenotype.\",\n      \"method\": \"Functional CSA binding assay in parasites with manipulated PTEF expression\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional assay in a single lab study; adhesion phenotype linked to PTEF expression level but single paper\",\n      \"pmids\": [\"28481333\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PTEF (PF3D7_0202400) is a non-canonical translation-enhancing factor in P. falciparum that is proteolytically processed by PfCalpain to release a C-terminal SAM-like domain, which shuttles to the cytoplasm, associates with ribosomes, and relieves upstream open reading frame-mediated repression of VAR2CSA translation, thereby controlling placental CSA-binding of infected erythrocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTEF (PF3D7_0202400) is a non-canonical translation-enhancing factor in Plasmodium falciparum that couples proteolytic processing to the translational control of the placental cytoadherence ligand VAR2CSA [#0]. PTEF is cleaved by PfCalpain, a step that liberates a C-terminal domain containing a sterile-alpha-motif (SAM)-like fold [#1]. This released C-terminal domain shuttles to the cytoplasm and associates directly with ribosomes, where it relieves upstream open reading frame (uORF)-mediated repression of the var2csa coding sequence, so that VAR2CSA protein output in var2csa-transcribing parasites scales with PTEF expression level [#0, #2]. The isolated C-terminal domain enhances translation in a heterologous system, establishing PTEF's intrinsic translation-enhancing activity [#3]. Through this control of VAR2CSA translation, PTEF activity governs the CSA-binding adhesion phenotype of infected erythrocytes [#4]. Beyond this processing-and-derepression mechanism defined in a single study, no further mechanistic detail on PTEF has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that VAR2CSA translation is not solely transcriptionally controlled but depends on a dedicated factor that overcomes uORF repression, identifying PTEF as that factor.\",\n      \"evidence\": \"Genetic manipulation of PTEF expression with measurement of VAR2CSA protein output in P. falciparum\",\n      \"pmids\": [\"28481333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how PTEF specifically recognizes the var2csa uORF versus other uORF-containing transcripts\", \"Quantitative relationship between PTEF dose and derepression not fully mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Explained how PTEF is activated, showing that its function requires PfCalpain cleavage to release a C-terminal SAM-like domain rather than acting as a full-length protein.\",\n      \"evidence\": \"In vitro and cellular proteolytic processing assays identifying PfCalpain, with domain characterization, in P. falciparum\",\n      \"pmids\": [\"28481333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger and timing of PfCalpain cleavage during the cell cycle not established\", \"Fate and function of the non-C-terminal portion of PTEF unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized the active fragment and its target, showing the cleaved C-terminal domain shuttles to the cytoplasm and binds ribosomes to derepress var2csa translation.\",\n      \"evidence\": \"Subcellular localization (cytoplasmic shuttling) and ribosome interaction/co-fractionation assays in P. falciparum\",\n      \"pmids\": [\"28481333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ribosomal contact site and stoichiometry not resolved\", \"Mechanism by which ribosome association overrides uORF stalling not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated the C-terminal domain has intrinsic translation-enhancing activity independent of the parasite context.\",\n      \"evidence\": \"Heterologous cell-free/non-Plasmodium translation assay with the PTEF C-terminal domain\",\n      \"pmids\": [\"28481333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterologous system may not recapitulate Plasmodium-specific cofactor requirements\", \"Not reconstituted with defined ribosomal components\", \"Single lab, single study\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected PTEF's translational role to a disease-relevant phenotype, showing PTEF activity controls CSA-binding of infected erythrocytes.\",\n      \"evidence\": \"Functional CSA binding assay in parasites with manipulated PTEF expression\",\n      \"pmids\": [\"28481333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of PTEF to adhesion phenotypes mediated by other PfEMP1 variants not tested\", \"In vivo relevance to placental sequestration not addressed\", \"Single paper\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTEF selectively targets particular uORF-containing mRNAs, the structural basis of its ribosome interaction, and its broader role in the parasite translatome remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of PTEF or its ribosome complex\", \"Transcript selectivity determinants unknown\", \"Whether PTEF regulates targets beyond var2csa uncharacterized\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0043022\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0045727\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006417\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0007155\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PfCalpain (protease that cleaves PTEF)\", \"ribosome (bound by the PTEF C-terminal domain)\", \"var2csa mRNA (translational target)\"],\n    \"other_free_text\": [\n      \"PTEF is proteolytically processed by PfCalpain to release a C-terminal SAM-like domain that constitutes the active translation-enhancing fragment [#1].\",\n      \"PTEF controls VAR2CSA protein output by relieving uORF-mediated translational repression, linking it to the CSA-binding placental adhesion phenotype of infected erythrocytes [#0, #4].\",\n      \"All current knowledge of PTEF derives from a single 2017 study; no independent replication or structural data are present in the corpus.\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0202400","name":null,"product":"translation-enhancing factor","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_0418700","name":null,"product":"gamete antigen 27/25, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"PTEF","evaluation":null}