{"gene":"PF3D7_0529300","run_date":"2026-09-07T10:55:52","timeline":{"discoveries":[{"year":2009,"finding":"PF3D7_0529300 (TIC22) localizes to the periphery of the apicoplast and is a membrane-associated (not integral) protein, expressed predominantly during the trophozoite stage of the asexual replication cycle.","method":"Endogenous-promoter-driven HA-tagging (3' replacement strategy) followed by immunofluorescence and fractionation in P. falciparum","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by epitope-tagging under endogenous promoter with fractionation to distinguish membrane-associated vs. integral; single lab, two orthogonal methods","pmids":["19502580"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"The crystal structure of TIC22 from P. falciparum (resolved to 2.15 Å using selenomethionine-labelled protein) reveals a fold conserved from cyanobacteria to plants, with a non-polar groove on each side of the molecule; these grooves enable TIC22 to act as a chaperone, maintaining cargo proteins in an unfolded conformation during transit across the apicoplast intermembrane space.","method":"X-ray crystallography (2.15 Å resolution, selenomethionine SAD phasing) combined with chaperone activity assays; functional essentiality and protein import role validated in T. gondii ortholog by genetic knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of P. falciparum TIC22 with functional chaperone assays; complementary genetic evidence of essentiality and import role from T. gondii ortholog provides multi-organism corroboration","pmids":["23027875"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"TIC22 from P. falciparum was successfully overproduced as a recombinant protein, purified, and crystallized, yielding diffraction data to 2.15 Å resolution, confirming that the soluble domain is amenable to structural studies.","method":"Recombinant protein overexpression, purification, and X-ray crystallography","journal":"Acta crystallographica. Section F, Structural biology and crystallization communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystallographic data collection confirmed; structure determination was reported as in progress at the time of this paper; single lab","pmids":["22442242"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0529300 (TIC22) is a membrane-associated apicoplast intermembrane-space protein, expressed at trophozoite stage, whose crystal structure reveals a conserved fold with non-polar grooves that confer chaperone activity, maintaining imported cargo proteins in an unfolded state during translocation into the apicoplast stroma."},"narrative":{"mechanistic_narrative":"PF3D7_0529300 (TIC22) is a component of the apicoplast protein import machinery in Plasmodium falciparum, functioning as a chaperone that maintains imported cargo in an unfolded state during translocation across the apicoplast intermembrane space [PMID:23027875]. It localizes to the periphery of the apicoplast as a membrane-associated (not integral) protein and is expressed predominantly during the trophozoite stage of the asexual cycle [PMID:19502580]. Its crystal structure, solved to 2.15 Å, reveals a fold conserved from cyanobacteria to plants bearing a non-polar groove on each side of the molecule that mediates its cargo-binding chaperone activity [PMID:23027875, PMID:22442242]. Beyond this membrane-associated intermembrane-space chaperone role, no further mechanistic detail—such as its specific import partners in P. falciparum—has been characterized in the available corpus.","teleology":[{"year":2009,"claim":"Establishing where TIC22 resides and how it associates with the organelle was the first step toward placing it in the apicoplast import pathway.","evidence":"Endogenous-promoter HA-tagging with immunofluorescence and fractionation in P. falciparum","pmids":["19502580"],"confidence":"Medium","gaps":["Does not define which membrane face or compartment TIC22 associates with","No functional role in import tested at this stage","Import partners in P. falciparum not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Producing recombinant TIC22 and obtaining diffraction-quality crystals demonstrated the soluble domain was tractable and set up structural determination of its fold.","evidence":"Recombinant overexpression, purification, and X-ray diffraction to 2.15 Å in P. falciparum TIC22","pmids":["22442242"],"confidence":"Medium","gaps":["Structure not yet solved at this reporting stage","No functional assay accompanying crystallization"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Solving the crystal structure revealed a conserved fold with non-polar grooves and linked it to chaperone activity, explaining how TIC22 could keep translocating cargo unfolded across the intermembrane space.","evidence":"2.15 Å X-ray structure (SeMet SAD) with chaperone activity assays for P. falciparum TIC22; essentiality and import role validated in the T. gondii ortholog by genetic knockdown","pmids":["23027875"],"confidence":"High","gaps":["Essentiality and direct import role shown in the T. gondii ortholog, not directly in P. falciparum TIC22","Specific cargo proteins bound by P. falciparum TIC22 not identified","Direct interaction with translocon components not defined in the corpus"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How TIC22 engages specific cargo and integrates with the apicoplast translocon machinery in P. falciparum remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified P. falciparum-specific cargo substrates","No characterized physical partners within the apicoplast import complex","Genetic essentiality demonstrated only for the ortholog, not directly for PF3D7_0529300"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":["Membrane-associated but not integral apicoplast peripheral protein, expressed predominantly at the trophozoite stage [#0]","Crystal structure at 2.15 Å reveals a fold conserved from cyanobacteria to plants with a non-polar groove on each side of the molecule [#1, #2]","Essentiality and direct protein-import role were validated in the T. gondii ortholog, not directly in P. falciparum TIC22 [#1]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"19502580","id":"PMC_19502580","title":"Characterization of two putative protein translocation components in the apicoplast of Plasmodium falciparum.","date":"2009","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/19502580","citation_count":60,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TIC22","PfTIC22"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23027875","id":"PMC_23027875","title":"Tic22 is an essential chaperone required for protein import into the apicoplast.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23027875","citation_count":55,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TIC22"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22442242","id":"PMC_22442242","title":"Overproduction, purification and crystallization of PfTic22, a component of the import apparatus from the apicoplast of Plasmodium falciparum.","date":"2012","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22442242","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TIC22","PfTIC22"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"39802746","id":"PMC_39802746","title":"Monitoring of enzymatic cleavage reaction of GST-fusion protein on biolayer interferometry sensor.","date":"2024","source":"Biophysics and physicobiology","url":"https://pubmed.ncbi.nlm.nih.gov/39802746","citation_count":0,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["TIC22"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4596,"output_tokens":894,"usd":0.013599,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5625,"output_tokens":1693,"usd":0.035225,"stage2_stop_reason":"end_turn"},"total_usd":0.048824,"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\": 2009,\n      \"finding\": \"PF3D7_0529300 (TIC22) localizes to the periphery of the apicoplast and is a membrane-associated (not integral) protein, expressed predominantly during the trophozoite stage of the asexual replication cycle.\",\n      \"method\": \"Endogenous-promoter-driven HA-tagging (3' replacement strategy) followed by immunofluorescence and fractionation in P. falciparum\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by epitope-tagging under endogenous promoter with fractionation to distinguish membrane-associated vs. integral; single lab, two orthogonal methods\",\n      \"pmids\": [\"19502580\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The crystal structure of TIC22 from P. falciparum (resolved to 2.15 Å using selenomethionine-labelled protein) reveals a fold conserved from cyanobacteria to plants, with a non-polar groove on each side of the molecule; these grooves enable TIC22 to act as a chaperone, maintaining cargo proteins in an unfolded conformation during transit across the apicoplast intermembrane space.\",\n      \"method\": \"X-ray crystallography (2.15 Å resolution, selenomethionine SAD phasing) combined with chaperone activity assays; functional essentiality and protein import role validated in T. gondii ortholog by genetic knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of P. falciparum TIC22 with functional chaperone assays; complementary genetic evidence of essentiality and import role from T. gondii ortholog provides multi-organism corroboration\",\n      \"pmids\": [\"23027875\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TIC22 from P. falciparum was successfully overproduced as a recombinant protein, purified, and crystallized, yielding diffraction data to 2.15 Å resolution, confirming that the soluble domain is amenable to structural studies.\",\n      \"method\": \"Recombinant protein overexpression, purification, and X-ray crystallography\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology and crystallization communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallographic data collection confirmed; structure determination was reported as in progress at the time of this paper; single lab\",\n      \"pmids\": [\"22442242\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0529300 (TIC22) is a membrane-associated apicoplast intermembrane-space protein, expressed at trophozoite stage, whose crystal structure reveals a conserved fold with non-polar grooves that confer chaperone activity, maintaining imported cargo proteins in an unfolded state during translocation into the apicoplast stroma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0529300 (TIC22) is a component of the apicoplast protein import machinery in Plasmodium falciparum, functioning as a chaperone that maintains imported cargo in an unfolded state during translocation across the apicoplast intermembrane space [#1]. It localizes to the periphery of the apicoplast as a membrane-associated (not integral) protein and is expressed predominantly during the trophozoite stage of the asexual cycle [#0]. Its crystal structure, solved to 2.15 Å, reveals a fold conserved from cyanobacteria to plants bearing a non-polar groove on each side of the molecule that mediates its cargo-binding chaperone activity [#1, #2]. Beyond this membrane-associated intermembrane-space chaperone role, no further mechanistic detail—such as its specific import partners in P. falciparum—has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing where TIC22 resides and how it associates with the organelle was the first step toward placing it in the apicoplast import pathway.\",\n      \"evidence\": \"Endogenous-promoter HA-tagging with immunofluorescence and fractionation in P. falciparum\",\n      \"pmids\": [\"19502580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define which membrane face or compartment TIC22 associates with\", \"No functional role in import tested at this stage\", \"Import partners in P. falciparum not identified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Producing recombinant TIC22 and obtaining diffraction-quality crystals demonstrated the soluble domain was tractable and set up structural determination of its fold.\",\n      \"evidence\": \"Recombinant overexpression, purification, and X-ray diffraction to 2.15 Å in P. falciparum TIC22\",\n      \"pmids\": [\"22442242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structure not yet solved at this reporting stage\", \"No functional assay accompanying crystallization\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Solving the crystal structure revealed a conserved fold with non-polar grooves and linked it to chaperone activity, explaining how TIC22 could keep translocating cargo unfolded across the intermembrane space.\",\n      \"evidence\": \"2.15 Å X-ray structure (SeMet SAD) with chaperone activity assays for P. falciparum TIC22; essentiality and import role validated in the T. gondii ortholog by genetic knockdown\",\n      \"pmids\": [\"23027875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Essentiality and direct import role shown in the T. gondii ortholog, not directly in P. falciparum TIC22\", \"Specific cargo proteins bound by P. falciparum TIC22 not identified\", \"Direct interaction with translocon components not defined in the corpus\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TIC22 engages specific cargo and integrates with the apicoplast translocon machinery in P. falciparum remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified P. falciparum-specific cargo substrates\", \"No characterized physical partners within the apicoplast import complex\", \"Genetic essentiality demonstrated only for the ortholog, not directly for PF3D7_0529300\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0009528\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0031977\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0045037\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": [\n      \"Membrane-associated but not integral apicoplast peripheral protein, expressed predominantly at the trophozoite stage [#0]\",\n      \"Crystal structure at 2.15 Å reveals a fold conserved from cyanobacteria to plants with a non-polar groove on each side of the molecule [#1, #2]\",\n      \"Essentiality and direct protein-import role were validated in the T. gondii ortholog, not directly in P. falciparum TIC22 [#1]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0529300","name":null,"product":"apicoplast TIC22 protein","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1243800","name":null,"product":"apicoplast TIC22 protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1003500","name":null,"product":"apicoplast TIC22 protein, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"TIC22","evaluation":null}