{"gene":"TG_220270","gene_symbol":"IMC6","run_date":"2026-09-06T08:22:39","timeline":{"discoveries":[{"year":2019,"finding":"IMC6 N-terminal domain is necessary for binding to ILP1, as demonstrated by photoactivatable unnatural amino acid (UAA) crosslinking; distinct regions of ILP1's C-terminal coiled-coil domain crosslink to IMC6, mapping the binding interface between these two cytoskeletal IMC proteins.","method":"Photoactivatable unnatural amino acid (UAA) crosslinking in native intracellular environment, domain deletion analyses","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in-cell photoreactive crosslinking with domain mapping, replicated and extended in subsequent studies","pmids":["31584943"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"Disruption of IMC6 causes striking morphological defects leading to aberrant invasion and replication, with surprisingly minor effects on motility, establishing IMC6 as essential for parasite structural integrity.","method":"Gene disruption (loss-of-function) with phenotypic readouts for morphology, invasion, replication, and motility","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple defined cellular phenotypic readouts in a single rigorous study, consistent with preprint version","pmids":["39264987"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"The alveolin domain of IMC6 alone is largely sufficient to restore localization and partially sufficient for function, as shown by deletion analyses.","method":"Deletion analyses with localization and functional complementation assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain deletion with both localization and functional readouts in a single rigorous study","pmids":["39264987"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"Photoactivatable UAA crosslinking to the IMC6 alveolin domain identified multiple direct binding interfaces between IMC6 and IMC3, and between IMC6 and ILP1, providing direct experimental evidence that the alveolin domain mediates protein-protein interactions and supports filament formation in the subpellicular network.","method":"Unnatural amino acid photoreactive crosslinking targeted to the alveolin domain, mass spectrometry identification of binding partners","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct crosslinking with domain-level binding interface mapping and MS identification, replicated across two publications (peer-reviewed and preprint)","pmids":["39264987","37609316"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2025,"finding":"IMC6 is loaded onto forming daughter buds earlier than IMC1 during replication, placing it upstream of IMC1 in the temporal hierarchy of alveolin recruitment to the nascent IMC.","method":"Expression timing and localization analysis during endodyogeny (bud formation)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — temporal localization observation from a preprint study focused on IMC1, single method, single lab","pmids":["40501855"],"is_preprint":true,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"IMC6 is a cytoskeletal alveolin protein of the Toxoplasma gondii inner membrane complex (IMC) whose alveolin domain directly mediates protein-protein interactions with IMC3 and ILP1 (via its N-terminal region), is largely sufficient for IMC localization, and is essential for maintaining parasite morphology, proper host cell invasion, and intracellular replication, with its loss causing striking structural defects but only minor motility impairment."},"narrative":{"mechanistic_narrative":"IMC6 is a cytoskeletal alveolin protein of the Toxoplasma gondii inner membrane complex (IMC) that maintains parasite structural integrity and supports the subpellicular filament network [PMID:39264987, PMID:37609316]. Its alveolin domain directly mediates protein-protein interactions, forming multiple binding interfaces with IMC3 and with ILP1, as mapped by photoactivatable unnatural amino acid crosslinking; the N-terminal region in particular engages the C-terminal coiled-coil domain of ILP1 [PMID:31584943, PMID:39264987, PMID:37609316]. This alveolin domain alone is largely sufficient to restore IMC localization and partially sufficient for function [PMID:39264987]. Disruption of IMC6 produces striking morphological defects that lead to aberrant host cell invasion and intracellular replication, while motility is only minorly affected, establishing IMC6 as essential for structural integrity rather than gliding [PMID:39264987].","teleology":[{"year":2019,"claim":"To establish how alveolin proteins physically assemble the IMC cytoskeleton, this work mapped the IMC6 binding interface, showing its N-terminal domain is necessary for binding ILP1.","evidence":"Photoactivatable unnatural amino acid crosslinking in the native intracellular environment with domain deletion analyses in T. gondii","pmids":["31584943"],"confidence":"High","gaps":["Did not map the full set of IMC6 partners beyond ILP1","Functional consequence of the IMC6-ILP1 interaction for parasite viability not tested"],"attribution":[]},{"year":2024,"claim":"To determine IMC6's cellular role, gene disruption showed it is required for parasite morphology, invasion, and replication but largely dispensable for motility, separating structural from motility functions of the IMC.","evidence":"Loss-of-function gene disruption with morphology, invasion, replication, and motility phenotypic readouts in T. gondii","pmids":["39264987"],"confidence":"High","gaps":["Molecular basis linking morphology defects to invasion/replication failure not resolved","Whether motility sparing reflects redundancy with other alveolins untested"],"attribution":[]},{"year":2024,"claim":"To localize the interaction and function to a specific region, deletion analyses established the alveolin domain as largely sufficient for IMC localization and partially sufficient for function, and crosslinking identified direct interfaces with both IMC3 and ILP1.","evidence":"Domain deletion with localization/functional complementation and UAA photoreactive crosslinking with mass spectrometry partner identification in T. gondii","pmids":["39264987","37609316"],"confidence":"High","gaps":["The portion of function not restored by the alveolin domain alone is unassigned","Stoichiometry and higher-order filament architecture of the IMC6-IMC3-ILP1 network not resolved"],"attribution":[]},{"year":2025,"claim":"To position IMC6 in the temporal assembly hierarchy of the nascent IMC, timing analysis showed it is loaded onto forming daughter buds earlier than IMC1, placing IMC6 upstream in alveolin recruitment during endodyogeny.","evidence":"Expression timing and localization analysis during bud formation in T. gondii (preprint)","pmids":["40501855"],"confidence":"Medium","gaps":["Preprint, single method and single lab observation","Mechanism determining early IMC6 recruitment unknown","Whether IMC6 recruitment is required for subsequent IMC1 loading not tested"],"attribution":[]},{"year":null,"claim":"How the IMC6-nucleated alveolin network is assembled into ordered subpellicular filaments and how its structural role mechanistically constrains invasion and replication remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the assembled filament network","Full partner set and assembly order beyond IMC3, ILP1, and IMC1 unresolved","Causal chain from morphology defect to invasion/replication failure uncharacterized"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Subpellicular network alveolin complex (IMC6-IMC3-ILP1)"],"partners":["IMC3","ILP1","IMC1"],"other_free_text":["The alveolin domain of IMC6 is largely sufficient for IMC localization and partially sufficient for function [#2].","IMC6 is loaded onto forming daughter buds earlier than IMC1 during endodyogeny, placing it upstream in alveolin recruitment [#4].","IMC6 disruption impairs morphology, invasion, and replication with only minor motility defects [#1]."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"31584943","id":"PMC_31584943","title":"A photoactivatable crosslinking system reveals protein interactions in the Toxoplasma gondii inner membrane complex.","date":"2019","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/31584943","citation_count":33,"is_preprint":false},{"pmid":"39264987","id":"PMC_39264987","title":"Alveolin proteins in the Toxoplasma inner membrane complex form a highly interconnected structure that maintains parasite shape and replication.","date":"2024","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/39264987","citation_count":10,"is_preprint":false},{"pmid":"37609316","id":"PMC_37609316","title":"The Toxoplasma subpellicular network is highly interconnected and defines parasite shape for efficient motility and replication.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37609316","citation_count":3,"is_preprint":false},{"pmid":"40501855","id":"PMC_40501855","title":"Toxoplasma IMC1 is a central component of the subpellicular network and plays critical roles in parasite morphology, replication, and infectivity.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40501855","citation_count":0,"is_preprint":false},{"pmid":"42113865","id":"PMC_42113865","title":"Toxoplasma IMC1 is a central component of the subpellicular network and plays critical roles in parasite morphology, replication, and infectivity.","date":"2026","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/42113865","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4879,"output_tokens":1178,"usd":0.016154,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6212,"output_tokens":2033,"usd":0.040942,"stage2_stop_reason":"end_turn"},"total_usd":0.057096,"stage1_batch_id":"msgbatch_01WgHz6kceqm573AGLyz57at","stage2_batch_id":"msgbatch_01LK4wDYj5zYquahv7gi9893","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"IMC6 N-terminal domain is necessary for binding to ILP1, as demonstrated by photoactivatable unnatural amino acid (UAA) crosslinking; distinct regions of ILP1's C-terminal coiled-coil domain crosslink to IMC6, mapping the binding interface between these two cytoskeletal IMC proteins.\",\n      \"method\": \"Photoactivatable unnatural amino acid (UAA) crosslinking in native intracellular environment, domain deletion analyses\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in-cell photoreactive crosslinking with domain mapping, replicated and extended in subsequent studies\",\n      \"pmids\": [\"31584943\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disruption of IMC6 causes striking morphological defects leading to aberrant invasion and replication, with surprisingly minor effects on motility, establishing IMC6 as essential for parasite structural integrity.\",\n      \"method\": \"Gene disruption (loss-of-function) with phenotypic readouts for morphology, invasion, replication, and motility\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple defined cellular phenotypic readouts in a single rigorous study, consistent with preprint version\",\n      \"pmids\": [\"39264987\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The alveolin domain of IMC6 alone is largely sufficient to restore localization and partially sufficient for function, as shown by deletion analyses.\",\n      \"method\": \"Deletion analyses with localization and functional complementation assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion with both localization and functional readouts in a single rigorous study\",\n      \"pmids\": [\"39264987\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Photoactivatable UAA crosslinking to the IMC6 alveolin domain identified multiple direct binding interfaces between IMC6 and IMC3, and between IMC6 and ILP1, providing direct experimental evidence that the alveolin domain mediates protein-protein interactions and supports filament formation in the subpellicular network.\",\n      \"method\": \"Unnatural amino acid photoreactive crosslinking targeted to the alveolin domain, mass spectrometry identification of binding partners\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct crosslinking with domain-level binding interface mapping and MS identification, replicated across two publications (peer-reviewed and preprint)\",\n      \"pmids\": [\"39264987\", \"37609316\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IMC6 is loaded onto forming daughter buds earlier than IMC1 during replication, placing it upstream of IMC1 in the temporal hierarchy of alveolin recruitment to the nascent IMC.\",\n      \"method\": \"Expression timing and localization analysis during endodyogeny (bud formation)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — temporal localization observation from a preprint study focused on IMC1, single method, single lab\",\n      \"pmids\": [\"40501855\"],\n      \"is_preprint\": true,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"IMC6 is a cytoskeletal alveolin protein of the Toxoplasma gondii inner membrane complex (IMC) whose alveolin domain directly mediates protein-protein interactions with IMC3 and ILP1 (via its N-terminal region), is largely sufficient for IMC localization, and is essential for maintaining parasite morphology, proper host cell invasion, and intracellular replication, with its loss causing striking structural defects but only minor motility impairment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IMC6 is a cytoskeletal alveolin protein of the Toxoplasma gondii inner membrane complex (IMC) that maintains parasite structural integrity and supports the subpellicular filament network [#1, #3]. Its alveolin domain directly mediates protein-protein interactions, forming multiple binding interfaces with IMC3 and with ILP1, as mapped by photoactivatable unnatural amino acid crosslinking; the N-terminal region in particular engages the C-terminal coiled-coil domain of ILP1 [#0, #3]. This alveolin domain alone is largely sufficient to restore IMC localization and partially sufficient for function [#2]. Disruption of IMC6 produces striking morphological defects that lead to aberrant host cell invasion and intracellular replication, while motility is only minorly affected, establishing IMC6 as essential for structural integrity rather than gliding [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"To establish how alveolin proteins physically assemble the IMC cytoskeleton, this work mapped the IMC6 binding interface, showing its N-terminal domain is necessary for binding ILP1.\",\n      \"evidence\": \"Photoactivatable unnatural amino acid crosslinking in the native intracellular environment with domain deletion analyses in T. gondii\",\n      \"pmids\": [\"31584943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the full set of IMC6 partners beyond ILP1\", \"Functional consequence of the IMC6-ILP1 interaction for parasite viability not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To determine IMC6's cellular role, gene disruption showed it is required for parasite morphology, invasion, and replication but largely dispensable for motility, separating structural from motility functions of the IMC.\",\n      \"evidence\": \"Loss-of-function gene disruption with morphology, invasion, replication, and motility phenotypic readouts in T. gondii\",\n      \"pmids\": [\"39264987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis linking morphology defects to invasion/replication failure not resolved\", \"Whether motility sparing reflects redundancy with other alveolins untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To localize the interaction and function to a specific region, deletion analyses established the alveolin domain as largely sufficient for IMC localization and partially sufficient for function, and crosslinking identified direct interfaces with both IMC3 and ILP1.\",\n      \"evidence\": \"Domain deletion with localization/functional complementation and UAA photoreactive crosslinking with mass spectrometry partner identification in T. gondii\",\n      \"pmids\": [\"39264987\", \"37609316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The portion of function not restored by the alveolin domain alone is unassigned\", \"Stoichiometry and higher-order filament architecture of the IMC6-IMC3-ILP1 network not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"To position IMC6 in the temporal assembly hierarchy of the nascent IMC, timing analysis showed it is loaded onto forming daughter buds earlier than IMC1, placing IMC6 upstream in alveolin recruitment during endodyogeny.\",\n      \"evidence\": \"Expression timing and localization analysis during bud formation in T. gondii (preprint)\",\n      \"pmids\": [\"40501855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single method and single lab observation\", \"Mechanism determining early IMC6 recruitment unknown\", \"Whether IMC6 recruitment is required for subsequent IMC1 loading not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the IMC6-nucleated alveolin network is assembled into ordered subpellicular filaments and how its structural role mechanistically constrains invasion and replication remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the assembled filament network\", \"Full partner set and assembly order beyond IMC3, ILP1, and IMC1 unresolved\", \"Causal chain from morphology defect to invasion/replication failure uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [0, 3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0070258\", \"supporting_discovery_ids\": [2, 3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0007034\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\"Subpellicular network alveolin complex (IMC6-IMC3-ILP1)\"],\n    \"partners\": [\"IMC3\", \"ILP1\", \"IMC1\"],\n    \"other_free_text\": [\n      \"The alveolin domain of IMC6 is largely sufficient for IMC localization and partially sufficient for function [#2].\",\n      \"IMC6 is loaded onto forming daughter buds earlier than IMC1 during endodyogeny, placing it upstream in alveolin recruitment [#4].\",\n      \"IMC6 disruption impairs morphology, invasion, and replication with only minor motility defects [#1].\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_220270","name":"IMC6","product":"alveolin domain containing intermediate filament IMC6","uniprot_acc":"S8F8Q1","chromosome":"TGME49_chrV","start_pos":249883},{"strain":"GT1","gene_id":"TGGT1_220270","name":null,"product":"alveolin domain containing intermediate filament IMC6","uniprot_acc":null,"chromosome":"TGGT1_chrV","start_pos":152699},{"strain":"RH88","gene_id":"TGRH88_023590","name":null,"product":"alveolin domain containing intermediate filament IMC6","uniprot_acc":null,"chromosome":"CM023086","start_pos":221475},{"strain":"VEG","gene_id":"TGVEG_220270","name":null,"product":"alveolin domain containing intermediate filament IMC6","uniprot_acc":"A0A0F7UR59","chromosome":"TGVEG_chrV","start_pos":171901}]}