{"gene":"PF3D7_1357000","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":1998,"finding":"P. falciparum, P. knowlesi, and P. berghei each contain two identical copies of the EF-1alpha gene arranged in a head-to-head orientation; both copies are expressed simultaneously during erythrocytic development at high levels, consistent with a gene dosage effect rather than functional specialization. The small intergenic region is proposed to contain either two strong promoters or a single bidirectional promoter.","method":"Genomic Southern blotting, sequence analysis of two gene copies, stage-specific expression profiling, codon-usage analysis","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic characterization and expression profiling in multiple Plasmodium species by a single lab; bidirectional promoter inferred but not directly tested by reporter assay","pmids":["9719506"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium knowlesi","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2003,"finding":"In P. falciparum-infected erythrocytes treated with chloroquine, ferriprotoporphyrin IX (FPIX) accumulates and binds to EF-1alpha (among other parasite proteins), as identified by affinity extraction of FPIX-binding proteins from parasite cytosol followed by protein sequencing.","method":"FPIX-affinity extraction from parasite cytosol, protein sequencing/identification","journal":"Parasite (Paris, France)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pulldown/affinity method, single lab; functional consequence of FPIX binding to EF-1alpha specifically was not established","pmids":["12669348"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"finding":"In P. berghei NK65, EF-1alpha is secreted via parasite-derived extracellular vesicles (EVs). EVs from EF-1alpha-deficient parasites failed to inhibit CD4+ T cell proliferative responses in vitro and in vivo, demonstrating that EF-1alpha carried by EVs contributes to immunosuppression. EVs from wild-type parasites dephosphorylated PLCγ1, Akt, and ERK in T cells; this effect was abrogated in EVs lacking EF-1alpha.","method":"Genetic knockout of EF-1alpha in P. berghei, EV isolation, in vitro T cell proliferation assay, in vivo delayed-type hypersensitivity assay, phosphorylation analysis of TCR signalling molecules","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetic knockouts with multiple orthogonal functional readouts (in vitro and in vivo), single lab","pmids":["30835870"],"is_preprint":false,"attribution":[{"species":"Plasmodium berghei","strain":"NK65"}]}],"current_model":"PF3D7_1357000 (EF-1alpha) exists as two identical, co-expressed gene copies in a head-to-head genomic arrangement in P. falciparum (and orthologs in P. knowlesi and P. berghei), consistent with a gene dosage function in translation; additionally, P. berghei EF-1alpha is secreted via extracellular vesicles and directly contributes to immunosuppression by inhibiting T cell receptor signalling (dephosphorylation of PLCγ1, Akt, and ERK), as shown by loss-of-function genetics, while chloroquine treatment causes FPIX to accumulate and bind to EF-1alpha in the parasite cytosol, though the functional consequence of this binding remains unresolved."},"narrative":{"mechanistic_narrative":"PF3D7_1357000 encodes elongation factor 1-alpha (EF-1alpha), which in P. falciparum, P. knowlesi, and P. berghei is present as two identical, simultaneously expressed gene copies arranged head-to-head, an organization consistent with a gene dosage function during erythrocytic development [PMID:9719506]. Beyond this genomic and expression characterization, the corpus provides two additional context-specific observations. In chloroquine-treated P. falciparum-infected erythrocytes, ferriprotoporphyrin IX (FPIX) accumulates in parasite cytosol and binds EF-1alpha, though the functional consequence of this binding is not established [PMID:12669348]. In P. berghei NK65, EF-1alpha is secreted via parasite-derived extracellular vesicles and is required for the vesicles' immunosuppressive activity: EVs lacking EF-1alpha fail to inhibit CD4+ T cell proliferation and no longer dephosphorylate the T cell receptor signalling molecules PLCγ1, Akt, and ERK [PMID:30835870]. No direct enzymatic or translational-mechanism data for PF3D7_1357000 itself has been characterized in the available corpus.","teleology":[{"year":1998,"claim":"It was unknown how EF-1alpha is encoded in Plasmodium; genomic characterization established that the gene exists as two identical, co-expressed copies in a head-to-head arrangement, implying a gene dosage rather than functional-specialization role.","evidence":"Genomic Southern blotting, two-copy sequence analysis, stage-specific expression profiling, and codon-usage analysis across three Plasmodium species","pmids":["9719506"],"confidence":"Medium","gaps":["The proposed bidirectional/dual promoter was inferred but not tested by reporter assay","No direct demonstration of translational elongation activity for the encoded protein","Functional necessity of the two-copy arrangement was not tested genetically"],"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium knowlesi","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2003,"claim":"To identify parasite targets of heme accumulation during chloroquine action, affinity extraction revealed that FPIX binds EF-1alpha in the parasite cytosol, placing EF-1alpha among the cytosolic FPIX-binding proteins.","evidence":"FPIX-affinity extraction from P. falciparum parasite cytosol followed by protein sequencing/identification","pmids":["12669348"],"confidence":"Low","gaps":["Single pulldown/affinity method from one lab, no reciprocal or in vitro binding validation","The functional consequence of FPIX binding to EF-1alpha was not established","Binding specificity relative to other cytosolic proteins not quantified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"It was unknown whether EF-1alpha has a role beyond translation; genetic knockout showed that EF-1alpha carried by parasite extracellular vesicles is required for host immunosuppression, revealing a moonlighting function in dampening T cell receptor signalling.","evidence":"EF-1alpha knockout in P. berghei NK65, EV isolation, in vitro CD4+ T cell proliferation assay, in vivo delayed-type hypersensitivity assay, and phosphorylation analysis of PLCγ1/Akt/ERK","pmids":["30835870"],"confidence":"Medium","gaps":["The molecular mechanism by which EF-1alpha drives dephosphorylation of TCR signalling molecules is not defined","Shown in P. berghei NK65; not demonstrated for the P. falciparum PF3D7_1357000 protein","How EF-1alpha is loaded into and secreted by extracellular vesicles is unknown"],"attribution":[{"species":"Plasmodium berghei","strain":"NK65"}]},{"year":null,"claim":"It remains unknown whether the canonical translational-elongation activity of PF3D7_1357000 is essential in P. falciparum and how its moonlighting immunosuppressive role and FPIX binding relate mechanistically to its core function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genetic essentiality or translational-activity data for PF3D7_1357000 in P. falciparum","No structural or biochemical mechanism linking FPIX binding to any functional outcome","The immunosuppressive phenotype has only been shown for the P. berghei ortholog"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["FERRIPROTOPORPHYRIN IX (FPIX) — BINDS EF-1ALPHA IN PARASITE CYTOSOL AFTER CHLOROQUINE TREATMENT [#1]"],"other_free_text":["Encoded as two identical, co-expressed head-to-head gene copies in P. falciparum, P. knowlesi, and P. berghei, consistent with a gene dosage effect [#0]","In P. berghei NK65, EF-1alpha secreted in extracellular vesicles is required for inhibition of CD4+ T cell proliferation and for dephosphorylation of PLCγ1, Akt, and ERK in T cells [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"9719506","id":"PMC_9719506","title":"Malaria parasites contain two identical copies of an elongation factor 1 alpha gene.","date":"1998","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9719506","citation_count":48,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["elongation factor 1-alpha"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"30835870","id":"PMC_30835870","title":"Histamine releasing factor and elongation factor 1 alpha secreted via malaria parasites extracellular vesicles promote immune evasion by inhibiting specific T cell responses.","date":"2019","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30835870","citation_count":38,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["elongation factor 1-alpha"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"12669348","id":"PMC_12669348","title":"The treatment of Plasmodium falciparum-infected erythrocytes with chloroquine leads to accumulation of ferriprotoporphyrin IX bound to particular parasite proteins and to the inhibition of the parasite's 6-phosphogluconate dehydrogenase.","date":"2003","source":"Parasite (Paris, France)","url":"https://pubmed.ncbi.nlm.nih.gov/12669348","citation_count":36,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["elongation factor 1-alpha"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28761783","id":"PMC_28761783","title":"Quantitative real-time PCR analysis of Anopheles dirus TEP1 and NOS during Plasmodium berghei infection, using three reference genes.","date":"2017","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/28761783","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["elongation factor 1-alpha"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"9803415","id":"PMC_9803415","title":"Characterisation of the Cdc2-related kinase 2 gene from Plasmodium knowlesi and P. berghei.","date":"1998","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/9803415","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["elongation factor 1-alpha"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41616650","id":"PMC_41616650","title":"Immunological response of using emulsifying elongation factor 1 alpha of Plasmodium falciparum-based vaccines in complete Freund's adjuvant.","date":"2026","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/41616650","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["elongation factor 1-alpha"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5858,"output_tokens":1102,"usd":0.017052,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5859,"output_tokens":2263,"usd":0.042935,"stage2_stop_reason":"end_turn"},"total_usd":0.059987,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"P. falciparum, P. knowlesi, and P. berghei each contain two identical copies of the EF-1alpha gene arranged in a head-to-head orientation; both copies are expressed simultaneously during erythrocytic development at high levels, consistent with a gene dosage effect rather than functional specialization. The small intergenic region is proposed to contain either two strong promoters or a single bidirectional promoter.\",\n      \"method\": \"Genomic Southern blotting, sequence analysis of two gene copies, stage-specific expression profiling, codon-usage analysis\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic characterization and expression profiling in multiple Plasmodium species by a single lab; bidirectional promoter inferred but not directly tested by reporter assay\",\n      \"pmids\": [\"9719506\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In P. falciparum-infected erythrocytes treated with chloroquine, ferriprotoporphyrin IX (FPIX) accumulates and binds to EF-1alpha (among other parasite proteins), as identified by affinity extraction of FPIX-binding proteins from parasite cytosol followed by protein sequencing.\",\n      \"method\": \"FPIX-affinity extraction from parasite cytosol, protein sequencing/identification\",\n      \"journal\": \"Parasite (Paris, France)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pulldown/affinity method, single lab; functional consequence of FPIX binding to EF-1alpha specifically was not established\",\n      \"pmids\": [\"12669348\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In P. berghei NK65, EF-1alpha is secreted via parasite-derived extracellular vesicles (EVs). EVs from EF-1alpha-deficient parasites failed to inhibit CD4+ T cell proliferative responses in vitro and in vivo, demonstrating that EF-1alpha carried by EVs contributes to immunosuppression. EVs from wild-type parasites dephosphorylated PLCγ1, Akt, and ERK in T cells; this effect was abrogated in EVs lacking EF-1alpha.\",\n      \"method\": \"Genetic knockout of EF-1alpha in P. berghei, EV isolation, in vitro T cell proliferation assay, in vivo delayed-type hypersensitivity assay, phosphorylation analysis of TCR signalling molecules\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetic knockouts with multiple orthogonal functional readouts (in vitro and in vivo), single lab\",\n      \"pmids\": [\"30835870\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"NK65\"}\n      ]\n    }\n  ],\n  \"current_model\": \"PF3D7_1357000 (EF-1alpha) exists as two identical, co-expressed gene copies in a head-to-head genomic arrangement in P. falciparum (and orthologs in P. knowlesi and P. berghei), consistent with a gene dosage function in translation; additionally, P. berghei EF-1alpha is secreted via extracellular vesicles and directly contributes to immunosuppression by inhibiting T cell receptor signalling (dephosphorylation of PLCγ1, Akt, and ERK), as shown by loss-of-function genetics, while chloroquine treatment causes FPIX to accumulate and bind to EF-1alpha in the parasite cytosol, though the functional consequence of this binding remains unresolved.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_1357000 encodes elongation factor 1-alpha (EF-1alpha), which in P. falciparum, P. knowlesi, and P. berghei is present as two identical, simultaneously expressed gene copies arranged head-to-head, an organization consistent with a gene dosage function during erythrocytic development [#0]. Beyond this genomic and expression characterization, the corpus provides two additional context-specific observations. In chloroquine-treated P. falciparum-infected erythrocytes, ferriprotoporphyrin IX (FPIX) accumulates in parasite cytosol and binds EF-1alpha, though the functional consequence of this binding is not established [#1]. In P. berghei NK65, EF-1alpha is secreted via parasite-derived extracellular vesicles and is required for the vesicles' immunosuppressive activity: EVs lacking EF-1alpha fail to inhibit CD4+ T cell proliferation and no longer dephosphorylate the T cell receptor signalling molecules PLCγ1, Akt, and ERK [#2]. No direct enzymatic or translational-mechanism data for PF3D7_1357000 itself has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"It was unknown how EF-1alpha is encoded in Plasmodium; genomic characterization established that the gene exists as two identical, co-expressed copies in a head-to-head arrangement, implying a gene dosage rather than functional-specialization role.\",\n      \"evidence\": \"Genomic Southern blotting, two-copy sequence analysis, stage-specific expression profiling, and codon-usage analysis across three Plasmodium species\",\n      \"pmids\": [\"9719506\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The proposed bidirectional/dual promoter was inferred but not tested by reporter assay\",\n        \"No direct demonstration of translational elongation activity for the encoded protein\",\n        \"Functional necessity of the two-copy arrangement was not tested genetically\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"To identify parasite targets of heme accumulation during chloroquine action, affinity extraction revealed that FPIX binds EF-1alpha in the parasite cytosol, placing EF-1alpha among the cytosolic FPIX-binding proteins.\",\n      \"evidence\": \"FPIX-affinity extraction from P. falciparum parasite cytosol followed by protein sequencing/identification\",\n      \"pmids\": [\"12669348\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single pulldown/affinity method from one lab, no reciprocal or in vitro binding validation\",\n        \"The functional consequence of FPIX binding to EF-1alpha was not established\",\n        \"Binding specificity relative to other cytosolic proteins not quantified\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unknown whether EF-1alpha has a role beyond translation; genetic knockout showed that EF-1alpha carried by parasite extracellular vesicles is required for host immunosuppression, revealing a moonlighting function in dampening T cell receptor signalling.\",\n      \"evidence\": \"EF-1alpha knockout in P. berghei NK65, EV isolation, in vitro CD4+ T cell proliferation assay, in vivo delayed-type hypersensitivity assay, and phosphorylation analysis of PLCγ1/Akt/ERK\",\n      \"pmids\": [\"30835870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The molecular mechanism by which EF-1alpha drives dephosphorylation of TCR signalling molecules is not defined\",\n        \"Shown in P. berghei NK65; not demonstrated for the P. falciparum PF3D7_1357000 protein\",\n        \"How EF-1alpha is loaded into and secreted by extracellular vesicles is unknown\"\n      ],\n      \"attribution\": [\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"NK65\"}\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the canonical translational-elongation activity of PF3D7_1357000 is essential in P. falciparum and how its moonlighting immunosuppressive role and FPIX binding relate mechanistically to its core function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No genetic essentiality or translational-activity data for PF3D7_1357000 in P. falciparum\",\n        \"No structural or biochemical mechanism linking FPIX binding to any functional outcome\",\n        \"The immunosuppressive phenotype has only been shown for the P. berghei ortholog\"\n      ],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003746\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0020037\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:1903561\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006414\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0050777\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Ferriprotoporphyrin IX (FPIX) — binds EF-1alpha in parasite cytosol after chloroquine treatment [#1]\"\n    ],\n    \"other_free_text\": [\n      \"Encoded as two identical, co-expressed head-to-head gene copies in P. falciparum, P. knowlesi, and P. berghei, consistent with a gene dosage effect [#0]\",\n      \"In P. berghei NK65, EF-1alpha secreted in extracellular vesicles is required for inhibition of CD4+ T cell proliferation and for dephosphorylation of PLCγ1, Akt, and ERK in T cells [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1357000","name":null,"product":"elongation factor 1-alpha","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1133300","name":null,"product":"elongation factor 1-alpha","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1114400","name":null,"product":"elongation factor 1-alpha, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"","evaluation":null}