{"gene":"PF3D7_0530900","run_date":"2026-09-07T10:55:52","timeline":{"discoveries":[{"year":2008,"finding":"The FH2 domain of PF3D7_0530900 (FRM1) nucleates actin polymerization in vitro and localizes to the barbed end of actin filaments during elongation, functioning as a potent actin nucleator; the protein localizes to the moving tight junction (moving junction) between the invading parasite and the host erythrocyte during merozoite invasion.","method":"In vitro actin polymerization assay using the FH2 domain; live imaging of GFP-tagged FRM1 tracking the moving junction during invasion","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of actin nucleation activity combined with direct live-imaging localization to the moving junction, replicated in Toxoplasma ortholog, multiple orthogonal methods in one study","pmids":["18329618"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"finding":"The FH2 domain of PF3D7_0530900 (FRM1) nucleates both mammalian and Plasmodium actin filaments in vitro; the lasso segment of the FH2 domain is required for assembly of functional FH2 dimers, as shown by solution structures determined with and without the lasso segment; Plasmodium profilin sequesters actin monomers but does not compete with FRM1 nucleation activity at equimolar profilin-actin ratios.","method":"In vitro actin polymerization assay; small-angle X-ray scattering (SAXS) solution structures of FH2 domain with and without lasso segment; functional dimerization assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of actin nucleation combined with solution structural determination and domain-deletion analysis establishing the lasso as essential for dimerization, multiple orthogonal methods in a single rigorous study","pmids":["22428073"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"finding":"PF3D7_0530900 (FRM1) is concentrated at the ends of elongating P. falciparum gametocytes, suggesting a role in the actin stabilization/nucleation at those sites; this localization was observed by super-resolution microscopy during gametocyte maturation.","method":"Super-resolution microscopy (immunofluorescence localization) in maturing gametocytes","journal":"Cellular microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment with no functional manipulation of FRM1 itself; functional consequence inferred but not directly tested","pmids":["25224798"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"Conditional deletion of PF3D7_0530900 (FRM1) establishes that it is essential for merozoite invasion and causes a delay in gametocyte stage progression, while having no major role in asexual cell division (unlike FRM2); treatment with the FH2 inhibitor SMIFH2 causes a multistage block in parasite development, confirming FRM1 formin activity is required in vivo.","method":"Conditional genetic deletion (DiCre excision system) with invasion assays and gametocyte staging; pharmacological inhibition with SMIFH2","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional knockout with specific phenotypic readouts (invasion block, gametocyte delay) plus pharmacological validation, two orthogonal methods in a single study","pmids":["37596377"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"PF3D7_0530900 (FRM1) is a Plasmodium falciparum formin whose FH2 domain—dimerization of which requires the lasso segment—nucleates actin filaments at their barbed ends in vitro; during merozoite invasion it tracks the moving junction between parasite and erythrocyte, and conditional deletion shows it is essential for invasion and contributes to gametocyte stage progression, while its actin-nucleating activity in vivo is supported by pharmacological blockade with the FH2 inhibitor SMIFH2."},"narrative":{"mechanistic_narrative":"PF3D7_0530900 (FRM1) is a Plasmodium falciparum formin that acts as a potent actin nucleator to drive the actin-dependent motility of merozoite invasion [PMID:18329618]. Its FH2 domain nucleates both Plasmodium and mammalian actin filaments in vitro and caps their barbed ends during elongation, and functional nucleation requires dimerization of the FH2 domain, which depends on the lasso segment established by solution structural analysis [PMID:18329618, PMID:22428073]. Plasmodium profilin sequesters actin monomers but does not compete with FRM1 nucleation at equimolar profilin-actin ratios, indicating FRM1 can nucleate against a profilin-buffered monomer pool [PMID:22428073]. During merozoite invasion FRM1 localizes to and tracks the moving tight junction between parasite and host erythrocyte [PMID:18329618], and conditional deletion establishes it is essential for invasion while contributing to gametocyte stage progression, with pharmacological FH2 blockade (SMIFH2) confirming its formin activity is required in vivo [PMID:37596377]. Beyond actin nucleation, moving-junction tracking, and these loss-of-function phenotypes, no further mechanistic detail for FRM1 has been characterized in the available corpus.","teleology":[{"year":2008,"claim":"Establishing whether FRM1 has intrinsic actin-nucleating activity and where it acts during invasion answered how the parasite generates directed actin assembly at the host-parasite interface.","evidence":"In vitro actin polymerization assay with the FH2 domain plus live imaging of GFP-tagged FRM1 tracking the moving junction during merozoite invasion","pmids":["18329618"],"confidence":"High","gaps":["Full-length protein regulation and how nucleation is spatially controlled at the junction not addressed","No direct genetic test of requirement in this study","Upstream activators or membrane anchors not identified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2012,"claim":"Determining the structural basis of FH2 activity answered how FRM1 assembles into the functional nucleating unit and whether profilin antagonizes it.","evidence":"In vitro polymerization assays with Plasmodium and mammalian actin, SAXS solution structures of the FH2 domain with and without the lasso segment, and domain-deletion dimerization assays","pmids":["22428073"],"confidence":"High","gaps":["High-resolution crystallographic structure not determined","Behavior at non-equimolar profilin-actin ratios not tested","Contribution of regions outside the FH2/lasso not addressed"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2014,"claim":"Localizing FRM1 in gametocytes probed whether its actin-organizing role extends beyond asexual invasion into sexual-stage morphogenesis.","evidence":"Super-resolution immunofluorescence localization of FRM1 to the ends of elongating gametocytes during maturation","pmids":["25224798"],"confidence":"Low","gaps":["Single localization experiment with no functional manipulation of FRM1","Actin nucleation at gametocyte ends inferred but not directly demonstrated","No link to a specific gametocyte morphogenetic outcome"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Conditional genetic ablation answered whether FRM1 is functionally required in vivo and distinguished its role from the sibling formin FRM2.","evidence":"DiCre conditional deletion with invasion assays and gametocyte staging, plus pharmacological inhibition with the FH2 inhibitor SMIFH2","pmids":["37596377"],"confidence":"High","gaps":["Molecular basis of the gametocyte progression delay not defined","SMIFH2 is not FRM1-specific, so multistage block cannot be attributed to FRM1 alone","Division of labor between FRM1 and FRM2 not mechanistically resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"How FRM1 is recruited to and regulated at the moving junction, and what upstream signals and partners control its nucleation during invasion and gametocytogenesis, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No identified activators, anchors, or regulatory partners of FRM1","No mechanistic link between FRM1 nucleation and gametocyte stage progression","No high-resolution structure of full-length FRM1"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["ACTIN (NUCLEATED/ELONGATED BY FRM1 FH2 DOMAIN) [#0, #1]","PLASMODIUM PROFILIN (DOES NOT COMPETE WITH FRM1 NUCLEATION AT EQUIMOLAR PROFILIN-ACTIN) [#1]"],"other_free_text":["FH2 dimerization requires the lasso segment, established by SAXS solution structures with and without the lasso [#1]","Essential for merozoite invasion and contributes to gametocyte stage progression by conditional (DiCre) deletion; distinct from sibling formin FRM2, which functions in asexual division [#3]","Formin activity required in vivo, confirmed by multistage developmental block with the FH2 inhibitor SMIFH2 [#3]","Concentrated at the ends of elongating gametocytes by super-resolution microscopy (Low confidence) [#2]"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"18329618","id":"PMC_18329618","title":"A malaria parasite formin regulates actin polymerization and localizes to the parasite-erythrocyte moving junction during invasion.","date":"2008","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/18329618","citation_count":97,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["formin 1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"25224798","id":"PMC_25224798","title":"Organization and function of an actin cytoskeleton in Plasmodium falciparum gametocytes.","date":"2014","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/25224798","citation_count":49,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["formin 1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"22428073","id":"PMC_22428073","title":"The lasso segment is required for functional dimerization of the Plasmodium formin 1 FH2 domain.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22428073","citation_count":18,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["formin 1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"37596377","id":"PMC_37596377","title":"Plasmodium falciparum formins are essential for invasion and sexual stage development.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/37596377","citation_count":6,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["FRM1"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4531,"output_tokens":1266,"usd":0.016292,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6123,"output_tokens":2362,"usd":0.044832,"stage2_stop_reason":"end_turn"},"total_usd":0.061124,"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\": 2008,\n      \"finding\": \"The FH2 domain of PF3D7_0530900 (FRM1) nucleates actin polymerization in vitro and localizes to the barbed end of actin filaments during elongation, functioning as a potent actin nucleator; the protein localizes to the moving tight junction (moving junction) between the invading parasite and the host erythrocyte during merozoite invasion.\",\n      \"method\": \"In vitro actin polymerization assay using the FH2 domain; live imaging of GFP-tagged FRM1 tracking the moving junction during invasion\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of actin nucleation activity combined with direct live-imaging localization to the moving junction, replicated in Toxoplasma ortholog, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18329618\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The FH2 domain of PF3D7_0530900 (FRM1) nucleates both mammalian and Plasmodium actin filaments in vitro; the lasso segment of the FH2 domain is required for assembly of functional FH2 dimers, as shown by solution structures determined with and without the lasso segment; Plasmodium profilin sequesters actin monomers but does not compete with FRM1 nucleation activity at equimolar profilin-actin ratios.\",\n      \"method\": \"In vitro actin polymerization assay; small-angle X-ray scattering (SAXS) solution structures of FH2 domain with and without lasso segment; functional dimerization assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of actin nucleation combined with solution structural determination and domain-deletion analysis establishing the lasso as essential for dimerization, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"22428073\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PF3D7_0530900 (FRM1) is concentrated at the ends of elongating P. falciparum gametocytes, suggesting a role in the actin stabilization/nucleation at those sites; this localization was observed by super-resolution microscopy during gametocyte maturation.\",\n      \"method\": \"Super-resolution microscopy (immunofluorescence localization) in maturing gametocytes\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment with no functional manipulation of FRM1 itself; functional consequence inferred but not directly tested\",\n      \"pmids\": [\"25224798\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional deletion of PF3D7_0530900 (FRM1) establishes that it is essential for merozoite invasion and causes a delay in gametocyte stage progression, while having no major role in asexual cell division (unlike FRM2); treatment with the FH2 inhibitor SMIFH2 causes a multistage block in parasite development, confirming FRM1 formin activity is required in vivo.\",\n      \"method\": \"Conditional genetic deletion (DiCre excision system) with invasion assays and gametocyte staging; pharmacological inhibition with SMIFH2\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional knockout with specific phenotypic readouts (invasion block, gametocyte delay) plus pharmacological validation, two orthogonal methods in a single study\",\n      \"pmids\": [\"37596377\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PF3D7_0530900 (FRM1) is a Plasmodium falciparum formin whose FH2 domain—dimerization of which requires the lasso segment—nucleates actin filaments at their barbed ends in vitro; during merozoite invasion it tracks the moving junction between parasite and erythrocyte, and conditional deletion shows it is essential for invasion and contributes to gametocyte stage progression, while its actin-nucleating activity in vivo is supported by pharmacological blockade with the FH2 inhibitor SMIFH2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PF3D7_0530900 (FRM1) is a Plasmodium falciparum formin that acts as a potent actin nucleator to drive the actin-dependent motility of merozoite invasion [#0]. Its FH2 domain nucleates both Plasmodium and mammalian actin filaments in vitro and caps their barbed ends during elongation, and functional nucleation requires dimerization of the FH2 domain, which depends on the lasso segment established by solution structural analysis [#0, #1]. Plasmodium profilin sequesters actin monomers but does not compete with FRM1 nucleation at equimolar profilin-actin ratios, indicating FRM1 can nucleate against a profilin-buffered monomer pool [#1]. During merozoite invasion FRM1 localizes to and tracks the moving tight junction between parasite and host erythrocyte [#0], and conditional deletion establishes it is essential for invasion while contributing to gametocyte stage progression, with pharmacological FH2 blockade (SMIFH2) confirming its formin activity is required in vivo [#3]. Beyond actin nucleation, moving-junction tracking, and these loss-of-function phenotypes, no further mechanistic detail for FRM1 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing whether FRM1 has intrinsic actin-nucleating activity and where it acts during invasion answered how the parasite generates directed actin assembly at the host-parasite interface.\",\n      \"evidence\": \"In vitro actin polymerization assay with the FH2 domain plus live imaging of GFP-tagged FRM1 tracking the moving junction during merozoite invasion\",\n      \"pmids\": [\"18329618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full-length protein regulation and how nucleation is spatially controlled at the junction not addressed\",\n        \"No direct genetic test of requirement in this study\",\n        \"Upstream activators or membrane anchors not identified\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Determining the structural basis of FH2 activity answered how FRM1 assembles into the functional nucleating unit and whether profilin antagonizes it.\",\n      \"evidence\": \"In vitro polymerization assays with Plasmodium and mammalian actin, SAXS solution structures of the FH2 domain with and without the lasso segment, and domain-deletion dimerization assays\",\n      \"pmids\": [\"22428073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"High-resolution crystallographic structure not determined\",\n        \"Behavior at non-equimolar profilin-actin ratios not tested\",\n        \"Contribution of regions outside the FH2/lasso not addressed\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Localizing FRM1 in gametocytes probed whether its actin-organizing role extends beyond asexual invasion into sexual-stage morphogenesis.\",\n      \"evidence\": \"Super-resolution immunofluorescence localization of FRM1 to the ends of elongating gametocytes during maturation\",\n      \"pmids\": [\"25224798\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single localization experiment with no functional manipulation of FRM1\",\n        \"Actin nucleation at gametocyte ends inferred but not directly demonstrated\",\n        \"No link to a specific gametocyte morphogenetic outcome\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Conditional genetic ablation answered whether FRM1 is functionally required in vivo and distinguished its role from the sibling formin FRM2.\",\n      \"evidence\": \"DiCre conditional deletion with invasion assays and gametocyte staging, plus pharmacological inhibition with the FH2 inhibitor SMIFH2\",\n      \"pmids\": [\"37596377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of the gametocyte progression delay not defined\",\n        \"SMIFH2 is not FRM1-specific, so multistage block cannot be attributed to FRM1 alone\",\n        \"Division of labor between FRM1 and FRM2 not mechanistically resolved\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FRM1 is recruited to and regulated at the moving junction, and what upstream signals and partners control its nucleation during invasion and gametocytogenesis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No identified activators, anchors, or regulatory partners of FRM1\",\n        \"No mechanistic link between FRM1 nucleation and gametocyte stage progression\",\n        \"No high-resolution structure of full-length FRM1\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051015\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0051017\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0015629\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0030050\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"actin (nucleated/elongated by FRM1 FH2 domain) [#0, #1]\",\n      \"Plasmodium profilin (does not compete with FRM1 nucleation at equimolar profilin-actin) [#1]\"\n    ],\n    \"other_free_text\": [\n      \"FH2 dimerization requires the lasso segment, established by SAXS solution structures with and without the lasso [#1]\",\n      \"Essential for merozoite invasion and contributes to gametocyte stage progression by conditional (DiCre) deletion; distinct from sibling formin FRM2, which functions in asexual division [#3]\",\n      \"Formin activity required in vivo, confirmed by multistage developmental block with the FH2 inhibitor SMIFH2 [#3]\",\n      \"Concentrated at the ends of elongating gametocytes by super-resolution microscopy (Low confidence) [#2]\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_0530900","name":null,"product":"formin 1","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1245300","name":null,"product":"formin 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1001800","name":null,"product":"formin 1, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"FRM1","evaluation":null}