{"gene":"TG_206580","gene_symbol":"FRM2","run_date":"2026-09-08T11:06:16","timeline":{"discoveries":[{"year":2012,"finding":"The FH1-FH2 domains of TgFRM2 dramatically enhance T. gondii actin (TgACTI) polymerization in vitro in the absence of profilin, making it one of the only protein factors known to initiate polymerization of this normally unstable actin. TgFRM2 FH1-FH2 also induces bundling of TgACTI filaments. TgPRF does not enhance but rather inhibits FRM2-driven polymerization by sequestering G-actin monomers.","method":"In vitro actin polymerization assays using purified FH1-FH2 domains of TgFRM2 and TgACTI","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple functional readouts (nucleation and bundling), single lab","pmids":["22397711"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2019,"finding":"FRM2 localizes to the apical juxtanuclear region of T. gondii and participates in apicoplast inheritance, as demonstrated by gene disruption combined with F-actin chromobody reporters showing loss of the apicoplast-associated actin population upon FRM2 disruption.","method":"Gene disruption combined with F-actin chromobody live imaging; subcellular localization by direct fluorescence","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic disruption with defined organelle inheritance phenotype plus direct localization imaging, single lab but two orthogonal methods","pmids":["30753127"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"TgFRM2 is a formin that localizes to the apical juxtanuclear region of T. gondii, where its FH1-FH2 domains nucleate and bundle parasite actin (TgACTI) filaments in vitro independently of profilin, and it drives a specific population of F-actin required for apicoplast inheritance during cell division."},"narrative":{"mechanistic_narrative":"TgFRM2 is a formin that drives actin-dependent apicoplast inheritance during Toxoplasma gondii cell division [PMID:30753127]. Its FH1-FH2 domains nucleate polymerization of the normally unstable parasite actin TgACTI in vitro without requiring profilin, making it one of the few known factors capable of initiating assembly of this actin, and they additionally bundle the resulting filaments; profilin (TgPRF) does not assist but instead inhibits FRM2-driven polymerization by sequestering G-actin monomers [PMID:22397711]. In the parasite, TgFRM2 localizes to the apical juxtanuclear region, where its disruption abolishes an apicoplast-associated F-actin population and impairs inheritance of this organelle [PMID:30753127]. Beyond nucleation, bundling, localization, and the apicoplast-inheritance phenotype, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2012,"claim":"Whether any factor could initiate polymerization of the intrinsically unstable T. gondii actin was unresolved; this established TgFRM2 as a bona fide nucleator and bundler of TgACTI and clarified profilin's antagonistic role.","evidence":"In vitro actin polymerization assays with purified TgFRM2 FH1-FH2 domains and TgACTI","pmids":["22397711"],"confidence":"High","gaps":["In vitro reconstitution does not establish the cellular context or filament population generated in vivo","No structural basis for nucleation or bundling defined","Role of full-length TgFRM2 beyond the FH1-FH2 fragment not tested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2019,"claim":"The cellular function of TgFRM2 was unknown; genetic disruption plus F-actin reporters localized it to the apical juxtanuclear region and tied it to a specific F-actin population required for apicoplast inheritance.","evidence":"Gene disruption combined with F-actin chromobody live imaging and direct fluorescence localization in T. gondii","pmids":["30753127"],"confidence":"High","gaps":["Mechanism linking the FRM2-generated F-actin to physical apicoplast segregation not resolved","Regulators recruiting or activating FRM2 at the juxtanuclear region unidentified","Whether the in vitro nucleation/bundling activity directly produces the apicoplast-associated actin population not demonstrated"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"How TgFRM2 is recruited and regulated at the apical juxtanuclear region, and how the F-actin it generates mechanically drives apicoplast segregation, remain open.","evidence":"","pmids":[],"confidence":"High","gaps":["No upstream regulators or recruitment mechanism identified","No structural model of the FRM2-actin interaction","Direct connection between in vitro bundling activity and organelle inheritance untested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["TGACTI (T. GONDII ACTIN)","TGPRF (T. GONDII PROFILIN, INHIBITORY)"],"other_free_text":["FH1-FH2 domains of TgFRM2 nucleate polymerization of the normally unstable TgACTI independently of profilin and bundle the resulting filaments [#0]","TgPRF inhibits FRM2-driven polymerization by sequestering G-actin monomers [#0]","Disruption of FRM2 abolishes an apicoplast-associated F-actin population and impairs apicoplast inheritance [#1]"]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"30753127","id":"PMC_30753127","title":"Three F-actin assembly centers regulate organelle inheritance, cell-cell communication and motility in Toxoplasma gondii.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30753127","citation_count":68,"is_preprint":false},{"pmid":"22397711","id":"PMC_22397711","title":"Toxoplasma gondii profilin acts primarily to sequester G-actin while formins efficiently nucleate actin filament formation in vitro.","date":"2012","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22397711","citation_count":37,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3306,"output_tokens":648,"usd":0.009819,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5319,"output_tokens":1797,"usd":0.03576,"stage2_stop_reason":"end_turn"},"total_usd":0.045579,"stage1_batch_id":"msgbatch_01WokvBYTB6JLnYrpD4rXnyV","stage2_batch_id":"msgbatch_01M7hsQDvz6AqVC9DLVjQzzc","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"The FH1-FH2 domains of TgFRM2 dramatically enhance T. gondii actin (TgACTI) polymerization in vitro in the absence of profilin, making it one of the only protein factors known to initiate polymerization of this normally unstable actin. TgFRM2 FH1-FH2 also induces bundling of TgACTI filaments. TgPRF does not enhance but rather inhibits FRM2-driven polymerization by sequestering G-actin monomers.\",\n      \"method\": \"In vitro actin polymerization assays using purified FH1-FH2 domains of TgFRM2 and TgACTI\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple functional readouts (nucleation and bundling), single lab\",\n      \"pmids\": [\"22397711\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FRM2 localizes to the apical juxtanuclear region of T. gondii and participates in apicoplast inheritance, as demonstrated by gene disruption combined with F-actin chromobody reporters showing loss of the apicoplast-associated actin population upon FRM2 disruption.\",\n      \"method\": \"Gene disruption combined with F-actin chromobody live imaging; subcellular localization by direct fluorescence\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic disruption with defined organelle inheritance phenotype plus direct localization imaging, single lab but two orthogonal methods\",\n      \"pmids\": [\"30753127\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"TgFRM2 is a formin that localizes to the apical juxtanuclear region of T. gondii, where its FH1-FH2 domains nucleate and bundle parasite actin (TgACTI) filaments in vitro independently of profilin, and it drives a specific population of F-actin required for apicoplast inheritance during cell division.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TgFRM2 is a formin that drives actin-dependent apicoplast inheritance during Toxoplasma gondii cell division [#1]. Its FH1-FH2 domains nucleate polymerization of the normally unstable parasite actin TgACTI in vitro without requiring profilin, making it one of the few known factors capable of initiating assembly of this actin, and they additionally bundle the resulting filaments; profilin (TgPRF) does not assist but instead inhibits FRM2-driven polymerization by sequestering G-actin monomers [#0]. In the parasite, TgFRM2 localizes to the apical juxtanuclear region, where its disruption abolishes an apicoplast-associated F-actin population and impairs inheritance of this organelle [#1]. Beyond nucleation, bundling, localization, and the apicoplast-inheritance phenotype, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether any factor could initiate polymerization of the intrinsically unstable T. gondii actin was unresolved; this established TgFRM2 as a bona fide nucleator and bundler of TgACTI and clarified profilin's antagonistic role.\",\n      \"evidence\": \"In vitro actin polymerization assays with purified TgFRM2 FH1-FH2 domains and TgACTI\",\n      \"pmids\": [\"22397711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vitro reconstitution does not establish the cellular context or filament population generated in vivo\",\n        \"No structural basis for nucleation or bundling defined\",\n        \"Role of full-length TgFRM2 beyond the FH1-FH2 fragment not tested\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The cellular function of TgFRM2 was unknown; genetic disruption plus F-actin reporters localized it to the apical juxtanuclear region and tied it to a specific F-actin population required for apicoplast inheritance.\",\n      \"evidence\": \"Gene disruption combined with F-actin chromobody live imaging and direct fluorescence localization in T. gondii\",\n      \"pmids\": [\"30753127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking the FRM2-generated F-actin to physical apicoplast segregation not resolved\",\n        \"Regulators recruiting or activating FRM2 at the juxtanuclear region unidentified\",\n        \"Whether the in vitro nucleation/bundling activity directly produces the apicoplast-associated actin population not demonstrated\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TgFRM2 is recruited and regulated at the apical juxtanuclear region, and how the F-actin it generates mechanically drives apicoplast segregation, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No upstream regulators or recruitment mechanism identified\",\n        \"No structural model of the FRM2-actin interaction\",\n        \"Direct connection between in vitro bundling activity and organelle inheritance untested\"\n      ],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051017\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0051764\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0003779\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020011\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007005\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TgACTI (T. gondii actin)\", \"TgPRF (T. gondii profilin, inhibitory)\"],\n    \"other_free_text\": [\n      \"FH1-FH2 domains of TgFRM2 nucleate polymerization of the normally unstable TgACTI independently of profilin and bundle the resulting filaments [#0]\",\n      \"TgPRF inhibits FRM2-driven polymerization by sequestering G-actin monomers [#0]\",\n      \"Disruption of FRM2 abolishes an apicoplast-associated F-actin population and impairs apicoplast inheritance [#1]\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_206580","name":"FRM2","product":"formin FRM2","uniprot_acc":"A0A125YM16","chromosome":"TGME49_chrVIIa","start_pos":811866},{"strain":"GT1","gene_id":"TGGT1_206580","name":null,"product":"formin FRM2","uniprot_acc":null,"chromosome":"TGGT1_chrVIIa","start_pos":788142},{"strain":"RH88","gene_id":"TGRH88_033440","name":null,"product":"formin FRM2","uniprot_acc":null,"chromosome":"CM023088","start_pos":892499},{"strain":"VEG","gene_id":"TGVEG_206580","name":null,"product":"formin FRM2","uniprot_acc":"V5BD13","chromosome":"TGVEG_chrVIIa","start_pos":869556}]}