{"gene":"TG_312630","gene_symbol":"GAC","run_date":"2026-09-08T15:15:13","timeline":{"discoveries":[{"year":2016,"finding":"GAC (glideosome-associated connector) binds to and stabilizes filamentous actin (F-actin), physically connecting micronemal adhesins (specifically TgMIC2) with the actomyosin system to mediate gliding motility, invasion, and egress.","method":"Co-immunoprecipitation, pulldown assays, functional genetic disruption with phenotypic readout (motility, invasion, egress)","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays combined with genetic disruption showing defined cellular phenotypes in both Toxoplasma and Plasmodium, multiple orthogonal methods in one study","pmids":["27978434"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"TgGAC localizes to the apical pole in invasive stages of Toxoplasma gondii, and this apical positioning depends on the apical lysine methyltransferase TgAKMT.","method":"Immunofluorescence localization, genetic disruption of TgAKMT with assessment of TgGAC mislocalization","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment linked to a functional regulator (TgAKMT), single lab with two orthogonal approaches","pmids":["27978434"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"finding":"The PH domain of GAC binds phosphatidic acid, a lipid mediator associated with microneme exocytosis, suggesting GAC acts as a lipid sensor to coordinate invasion.","method":"Lipid-binding assay (PH domain interaction with phosphatidic acid)","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct lipid-binding assay reported in a single study, single lab, single method for this specific finding","pmids":["27978434"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2019,"finding":"The flux of F-actin driven by formin FRM1 that is required for motility, invasion, and egress persists in the absence of GAC, indicating GAC is not required for F-actin flux initiation per se but acts downstream to couple actin to adhesins.","method":"F-actin chromobody live imaging combined with GAC gene disruption","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-imaging chromobody reporter combined with genetic disruption, single lab, directly informative negative result about GAC's role in actin flux","pmids":["30753127"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"finding":"Crystal structure of Toxoplasma gondii GAC reveals a unique supercoiled armadillo repeat region that adopts a closed ring conformation; solution studies indicate GAC can adopt multiple conformations from closed to open and extended, with distinct membrane and F-actin binding interfaces.","method":"X-ray crystallography, solution biophysics (SAXS/SEC), F-actin and membrane binding assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with solution characterization and functional binding interface mapping in a single rigorous study","pmids":["37014051"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"TgGAC is an armadillo/PH domain-containing apical protein whose supercoiled armadillo repeat region can transition between closed and open conformations; it bridges the actomyosin motor to surface transmembrane adhesins (TgMIC2) by binding and stabilizing F-actin and membranes (via phosphatidic acid recognition by its PH domain), thereby transmitting myosin-generated force to the substrate to power gliding motility, invasion, and egress, with its apical localization regulated by the methyltransferase TgAKMT."},"narrative":{"mechanistic_narrative":"GAC (glideosome-associated connector) is an apical armadillo/PH domain protein that mechanically couples the actomyosin motor to surface adhesins to power gliding motility, host-cell invasion, and egress in apicomplexan parasites [PMID:27978434]. It binds and stabilizes filamentous actin and physically bridges F-actin to the micronemal transmembrane adhesin TgMIC2, thereby transmitting myosin-generated force to the substrate; genetic disruption of GAC abolishes motility, invasion, and egress [PMID:27978434]. GAC acts downstream of actin polymerization rather than in its initiation: FRM1-driven F-actin flux persists in GAC-null parasites, defining GAC as the connector that engages this flux with adhesins rather than the source of the flux [PMID:30753127]. Its PH domain recognizes phosphatidic acid, a lipid signal linked to microneme exocytosis, positioning GAC as a lipid sensor that coordinates the motor-adhesin coupling with invasion signaling [PMID:27978434]. Structurally, GAC is built from a supercoiled armadillo repeat region that crystallizes as a closed ring but can transition through open and extended conformations bearing distinct membrane- and F-actin-binding interfaces, providing a conformational basis for its bridging function [PMID:37014051]. In Toxoplasma gondii, GAC is concentrated at the apical pole of invasive stages, and this positioning requires the apical lysine methyltransferase TgAKMT [PMID:27978434].","teleology":[{"year":2016,"claim":"Established GAC as the physical connector coupling surface adhesins to the actomyosin motor, answering how force is transmitted from the internal motor to the substrate during gliding.","evidence":"Co-immunoprecipitation, pulldown, and F-actin binding assays with genetic disruption scoring motility, invasion, and egress in Toxoplasma and Plasmodium","pmids":["27978434"],"confidence":"High","gaps":["Structural basis of the actin- and adhesin-binding interfaces not resolved","Stoichiometry and dynamics of the connector complex undefined"],"attribution":[{"species":"Toxoplasma gondii","strain":""},{"species":"Plasmodium berghei","strain":""}]},{"year":2016,"claim":"Defined how GAC is spatially restricted to the site of invasion by identifying TgAKMT as the regulator of its apical positioning.","evidence":"Immunofluorescence localization and TgAKMT genetic disruption assessing GAC mislocalization in Toxoplasma gondii","pmids":["27978434"],"confidence":"High","gaps":["Whether TgAKMT methylates GAC directly is not shown","Molecular mechanism linking methylation to apical anchoring unknown"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2016,"claim":"Suggested GAC integrates a lipid signal into invasion by showing its PH domain binds phosphatidic acid, a mediator of microneme exocytosis.","evidence":"Lipid-binding assay of the isolated PH domain","pmids":["27978434"],"confidence":"Medium","gaps":["Single lipid-binding assay from one lab","Functional consequence of PH-lipid binding for invasion not directly tested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2019,"claim":"Placed GAC downstream of actin polymerization by showing FRM1-driven F-actin flux persists without GAC, distinguishing the connector role from flux initiation.","evidence":"F-actin chromobody live imaging combined with GAC gene disruption in Toxoplasma gondii","pmids":["30753127"],"confidence":"Medium","gaps":["Live-imaging chromobody negative result from a single lab","How GAC engages flowing actin to transmit force not resolved"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2023,"claim":"Provided a conformational framework for GAC's bridging activity by resolving its supercoiled armadillo repeat ring and its capacity to adopt open/extended states with distinct binding interfaces.","evidence":"X-ray crystallography, SAXS/SEC solution biophysics, and F-actin/membrane binding interface mapping in Toxoplasma gondii","pmids":["37014051"],"confidence":"High","gaps":["Trigger and timing of the closed-to-open transition in vivo unknown","Structure of GAC bound simultaneously to actin, membrane, and MIC2 not determined"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":null,"claim":"How GAC's conformational transitions, lipid sensing, and TgAKMT-dependent apical positioning are coordinated in time to trigger force transmission during invasion remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking PH-domain lipid binding to conformational opening","Direct substrate relationship between TgAKMT and GAC untested"],"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["Glideosome (actomyosin motor connector)"],"partners":["F-ACTIN","TGMIC2 (MICRONEMAL ADHESIN)","TGAKMT (APICAL LYSINE METHYLTRANSFERASE, REGULATOR OF APICAL LOCALIZATION)","PHOSPHATIDIC ACID (PH-DOMAIN LIGAND)"],"other_free_text":["Contains a supercoiled armadillo repeat region that adopts a closed ring and can transition to open/extended conformations with distinct F-actin and membrane binding interfaces [#4].","Acts downstream of FRM1-driven F-actin flux, coupling actin to adhesins rather than initiating flux [#3]."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"27978434","id":"PMC_27978434","title":"An Apicomplexan Actin-Binding Protein Serves as a Connector and Lipid Sensor to Coordinate Motility and Invasion.","date":"2016","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/27978434","citation_count":86,"is_preprint":false},{"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":"37014051","id":"PMC_37014051","title":"Structural and regulatory insights into the glideosome-associated connector from Toxoplasma gondii.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37014051","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3553,"output_tokens":1305,"usd":0.015117,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6303,"output_tokens":2713,"usd":0.04967,"stage2_stop_reason":"end_turn"},"total_usd":0.064787,"stage1_batch_id":"msgbatch_01S6GjoYQm8LTPUsdhASdqag","stage2_batch_id":"msgbatch_01VX63RTMdBJqsG6gQMqoCjz","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2016,\n      \"finding\": \"GAC (glideosome-associated connector) binds to and stabilizes filamentous actin (F-actin), physically connecting micronemal adhesins (specifically TgMIC2) with the actomyosin system to mediate gliding motility, invasion, and egress.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, functional genetic disruption with phenotypic readout (motility, invasion, egress)\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays combined with genetic disruption showing defined cellular phenotypes in both Toxoplasma and Plasmodium, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27978434\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TgGAC localizes to the apical pole in invasive stages of Toxoplasma gondii, and this apical positioning depends on the apical lysine methyltransferase TgAKMT.\",\n      \"method\": \"Immunofluorescence localization, genetic disruption of TgAKMT with assessment of TgGAC mislocalization\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment linked to a functional regulator (TgAKMT), single lab with two orthogonal approaches\",\n      \"pmids\": [\"27978434\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The PH domain of GAC binds phosphatidic acid, a lipid mediator associated with microneme exocytosis, suggesting GAC acts as a lipid sensor to coordinate invasion.\",\n      \"method\": \"Lipid-binding assay (PH domain interaction with phosphatidic acid)\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct lipid-binding assay reported in a single study, single lab, single method for this specific finding\",\n      \"pmids\": [\"27978434\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The flux of F-actin driven by formin FRM1 that is required for motility, invasion, and egress persists in the absence of GAC, indicating GAC is not required for F-actin flux initiation per se but acts downstream to couple actin to adhesins.\",\n      \"method\": \"F-actin chromobody live imaging combined with GAC gene disruption\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-imaging chromobody reporter combined with genetic disruption, single lab, directly informative negative result about GAC's role in actin flux\",\n      \"pmids\": [\"30753127\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal structure of Toxoplasma gondii GAC reveals a unique supercoiled armadillo repeat region that adopts a closed ring conformation; solution studies indicate GAC can adopt multiple conformations from closed to open and extended, with distinct membrane and F-actin binding interfaces.\",\n      \"method\": \"X-ray crystallography, solution biophysics (SAXS/SEC), F-actin and membrane binding assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with solution characterization and functional binding interface mapping in a single rigorous study\",\n      \"pmids\": [\"37014051\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}\n      ]\n    }\n  ],\n  \"current_model\": \"TgGAC is an armadillo/PH domain-containing apical protein whose supercoiled armadillo repeat region can transition between closed and open conformations; it bridges the actomyosin motor to surface transmembrane adhesins (TgMIC2) by binding and stabilizing F-actin and membranes (via phosphatidic acid recognition by its PH domain), thereby transmitting myosin-generated force to the substrate to power gliding motility, invasion, and egress, with its apical localization regulated by the methyltransferase TgAKMT.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GAC (glideosome-associated connector) is an apical armadillo/PH domain protein that mechanically couples the actomyosin motor to surface adhesins to power gliding motility, host-cell invasion, and egress in apicomplexan parasites [#0]. It binds and stabilizes filamentous actin and physically bridges F-actin to the micronemal transmembrane adhesin TgMIC2, thereby transmitting myosin-generated force to the substrate; genetic disruption of GAC abolishes motility, invasion, and egress [#0]. GAC acts downstream of actin polymerization rather than in its initiation: FRM1-driven F-actin flux persists in GAC-null parasites, defining GAC as the connector that engages this flux with adhesins rather than the source of the flux [#3]. Its PH domain recognizes phosphatidic acid, a lipid signal linked to microneme exocytosis, positioning GAC as a lipid sensor that coordinates the motor-adhesin coupling with invasion signaling [#2]. Structurally, GAC is built from a supercoiled armadillo repeat region that crystallizes as a closed ring but can transition through open and extended conformations bearing distinct membrane- and F-actin-binding interfaces, providing a conformational basis for its bridging function [#4]. In Toxoplasma gondii, GAC is concentrated at the apical pole of invasive stages, and this positioning requires the apical lysine methyltransferase TgAKMT [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established GAC as the physical connector coupling surface adhesins to the actomyosin motor, answering how force is transmitted from the internal motor to the substrate during gliding.\",\n      \"evidence\": \"Co-immunoprecipitation, pulldown, and F-actin binding assays with genetic disruption scoring motility, invasion, and egress in Toxoplasma and Plasmodium\",\n      \"pmids\": [\"27978434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the actin- and adhesin-binding interfaces not resolved\", \"Stoichiometry and dynamics of the connector complex undefined\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined how GAC is spatially restricted to the site of invasion by identifying TgAKMT as the regulator of its apical positioning.\",\n      \"evidence\": \"Immunofluorescence localization and TgAKMT genetic disruption assessing GAC mislocalization in Toxoplasma gondii\",\n      \"pmids\": [\"27978434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TgAKMT methylates GAC directly is not shown\", \"Molecular mechanism linking methylation to apical anchoring unknown\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Suggested GAC integrates a lipid signal into invasion by showing its PH domain binds phosphatidic acid, a mediator of microneme exocytosis.\",\n      \"evidence\": \"Lipid-binding assay of the isolated PH domain\",\n      \"pmids\": [\"27978434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lipid-binding assay from one lab\", \"Functional consequence of PH-lipid binding for invasion not directly tested\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed GAC downstream of actin polymerization by showing FRM1-driven F-actin flux persists without GAC, distinguishing the connector role from flux initiation.\",\n      \"evidence\": \"F-actin chromobody live imaging combined with GAC gene disruption in Toxoplasma gondii\",\n      \"pmids\": [\"30753127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Live-imaging chromobody negative result from a single lab\", \"How GAC engages flowing actin to transmit force not resolved\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided a conformational framework for GAC's bridging activity by resolving its supercoiled armadillo repeat ring and its capacity to adopt open/extended states with distinct binding interfaces.\",\n      \"evidence\": \"X-ray crystallography, SAXS/SEC solution biophysics, and F-actin/membrane binding interface mapping in Toxoplasma gondii\",\n      \"pmids\": [\"37014051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger and timing of the closed-to-open transition in vivo unknown\", \"Structure of GAC bound simultaneously to actin, membrane, and MIC2 not determined\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GAC's conformational transitions, lipid sensing, and TgAKMT-dependent apical positioning are coordinated in time to trigger force transmission during invasion remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking PH-domain lipid binding to conformational opening\", \"Direct substrate relationship between TgAKMT and GAC untested\"],\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0051015\", \"supporting_discovery_ids\": [0, 4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0070300\", \"supporting_discovery_ids\": [2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0005543\", \"supporting_discovery_ids\": [2, 4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0020009\", \"supporting_discovery_ids\": [1], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0071693\", \"supporting_discovery_ids\": [0, 3], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0052126\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}, {\"species\": \"Plasmodium berghei\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [\"Glideosome (actomyosin motor connector)\"],\n    \"partners\": [\"F-actin\", \"TgMIC2 (micronemal adhesin)\", \"TgAKMT (apical lysine methyltransferase, regulator of apical localization)\", \"phosphatidic acid (PH-domain ligand)\"],\n    \"other_free_text\": [\n      \"Contains a supercoiled armadillo repeat region that adopts a closed ring and can transition to open/extended conformations with distinct F-actin and membrane binding interfaces [#4].\",\n      \"Acts downstream of FRM1-driven F-actin flux, coupling actin to adhesins rather than initiating flux [#3].\"\n    ]\n  },\n  \"strain_conflicts\": []\n}","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_312630","name":"GAC","product":"glideosome-associated connector GAC","uniprot_acc":"S8ERI9","chromosome":"TGME49_chrXI","start_pos":2840343},{"strain":"GT1","gene_id":"TGGT1_312630","name":null,"product":"putative anonymous antigen-1","uniprot_acc":null,"chromosome":"TGGT1_chrXI","start_pos":2804165},{"strain":"RH88","gene_id":"TGRH88_051880","name":null,"product":"putative anonymous antigen-1","uniprot_acc":null,"chromosome":"CM023092","start_pos":2889857},{"strain":"VEG","gene_id":"TGVEG_312630","name":null,"product":"putative anonymous antigen-1","uniprot_acc":"A0A125YHE8","chromosome":"TGVEG_chrXI","start_pos":2853391}]}