{"gene":"TG_290160","gene_symbol":"SORTLR","run_date":"2026-09-08T14:08:30","timeline":{"discoveries":[{"year":2012,"finding":"TgSORTLR is a transmembrane protein that resides within Golgi-endosomal related compartments in Toxoplasma gondii.","method":"Subcellular fractionation and localization experiments","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiment with functional consequence, 108 citations, multiple orthogonal methods in one study","pmids":["22607804"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2012,"finding":"The lumenal domain of TgSORTLR specifically interacts with rhoptry and microneme proteins, establishing it as a cargo receptor for apical secretory organelle proteins.","method":"Co-immunoprecipitation / binding interaction assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, functionally validated by dominant-negative and conditional ablation experiments, multiple orthogonal methods","pmids":["22607804"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2012,"finding":"The cytoplasmic tail of TgSORTLR recruits cytosolic sorting machinery involved in both anterograde and retrograde protein transport.","method":"Protein interaction assays / domain dissection","journal":"Cell host & microbe","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction demonstrated in single study, but mechanism of recruitment not fully resolved at atomic level from abstract","pmids":["22607804"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2012,"finding":"Ectopic expression of the N-terminal TgSORTLR lumenal domain acts as a dominant negative, causing mislocalization of both endogenous TgSORTLR and rhoptry/microneme proteins, confirming the lumenal domain mediates cargo capture.","method":"Dominant-negative overexpression with immunofluorescence readout","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative experiment with defined molecular phenotype, part of multi-method study with 108 citations","pmids":["22607804"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2012,"finding":"Conditional ablation of TgSORTLR disrupts rhoptry and microneme biogenesis, inhibits parasite motility, and blocks both invasion into and egress from host cells, demonstrating TgSORTLR is essential for apical organelle formation and host infection.","method":"Conditional knockdown / genetic ablation with phenotypic readouts (organelle morphology, motility, invasion, egress assays)","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional loss-of-function with multiple specific cellular phenotypes, rigorously controlled, 108 citations","pmids":["22607804"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"The Vps10, sortilin-C, and sortilin-M subdomains of TgSORTLR are the binding regions for intracellular cargo protein transport, as determined by bio-layer interferometry with individual domain constructs.","method":"Immunoprecipitation, mass spectrometry, bio-layer interferometry with domain constructs","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay (bio-layer interferometry) with domain dissection, single lab, limited replication","pmids":["38439083"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]},{"year":2024,"finding":"The small-molecule inhibitor AF38469 binds to the Vps10 subdomain of TgSORTLR and inhibits parasite invasion, replication, and intracellular growth in vitro and in a mouse infection model.","method":"Bio-layer interferometry (binding site determination), in vitro invasion/replication assays, mouse infection model","journal":"Parasites & vectors","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding site identified and functional inhibition demonstrated in vitro and in vivo, single lab study","pmids":["38439083"],"is_preprint":false,"attribution":[{"species":"Toxoplasma gondii","strain":""}]}],"current_model":"TgSORTLR is a transmembrane receptor residing in Golgi-endosomal compartments whose lumenal Vps10, sortilin-C, and sortilin-M subdomains capture rhoptry and microneme cargo proteins for anterograde trafficking, while its cytoplasmic tail recruits cytosolic sorting machinery for retrograde transport, and conditional loss of TgSORTLR abolishes apical organelle biogenesis, parasite motility, and host cell invasion/egress."},"narrative":{"mechanistic_narrative":"TgSORTLR is a transmembrane cargo receptor of the Golgi-endosomal system in Toxoplasma gondii that governs biogenesis of the apical secretory organelles required for host infection [PMID:22607804]. Its lumenal domain captures rhoptry and microneme proteins for anterograde delivery, a cargo-binding function localized to the Vps10, sortilin-C, and sortilin-M subdomains [PMID:22607804, PMID:38439083], while its cytoplasmic tail recruits cytosolic sorting machinery for anterograde and retrograde transport [PMID:22607804]. Ectopic expression of the lumenal domain acts as a dominant negative, mislocalizing both endogenous TgSORTLR and its rhoptry/microneme cargo [PMID:22607804], and conditional ablation disrupts rhoptry and microneme biogenesis and abolishes parasite motility, host cell invasion, and egress [PMID:22607804], establishing TgSORTLR as essential for infection. The Vps10 subdomain is druggable: the small molecule AF38469 binds it and inhibits invasion, replication, and intracellular growth in vitro and in a mouse infection model [PMID:38439083]. Beyond these findings, the atomic-level mechanism of cytosolic machinery recruitment and the full cargo repertoire have not been characterized in the available corpus.","teleology":[{"year":2012,"claim":"Establishing where TgSORTLR resides and what it binds answered whether Toxoplasma uses a dedicated receptor to sort apical organelle cargo, defining it as a cargo receptor in the secretory pathway.","evidence":"Subcellular fractionation/localization plus co-immunoprecipitation binding assays in T. gondii","pmids":["22607804"],"confidence":"High","gaps":["Precise cargo repertoire beyond rhoptry/microneme proteins not enumerated","Kinetics and affinity of cargo binding not quantified in this study"],"attribution":[]},{"year":2012,"claim":"Domain dissection tested which part of the receptor performs each trafficking task, showing the lumenal domain captures cargo while the cytoplasmic tail engages cytosolic sorting machinery for bidirectional transport.","evidence":"Protein interaction assays and domain dissection; dominant-negative overexpression with immunofluorescence readout in T. gondii","pmids":["22607804"],"confidence":"High","gaps":["Identity of the cytosolic sorting adaptors recruited by the tail not resolved","Atomic-level basis of tail-machinery interaction unknown"],"attribution":[]},{"year":2012,"claim":"Conditional ablation tested whether TgSORTLR is functionally required, demonstrating it is essential for apical organelle biogenesis and the motility-dependent invasion/egress cycle.","evidence":"Conditional knockdown/genetic ablation with organelle morphology, motility, invasion, and egress assays in T. gondii","pmids":["22607804"],"confidence":"High","gaps":["Whether the invasion defect is solely secondary to organelle loss or also reflects direct trafficking roles not separated","Effect on other secretory pathways not addressed"],"attribution":[]},{"year":2024,"claim":"Mapping cargo binding to specific lumenal subdomains refined the receptor mechanism and identified a druggable pocket, converting mechanistic knowledge into a therapeutic target.","evidence":"Immunoprecipitation, mass spectrometry, and bio-layer interferometry with individual domain constructs; AF38469 binding, in vitro invasion/replication assays, and mouse infection model in T. gondii","pmids":["38439083"],"confidence":"Medium","gaps":["Single-lab study with limited replication","Structural basis of AF38469-Vps10 binding not resolved at atomic level","Selectivity of AF38469 for parasite versus host sortilin not established"],"attribution":[]},{"year":null,"claim":"The identity of the cytosolic sorting adaptors recruited by the TgSORTLR tail and the structural basis of cargo and inhibitor binding remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of cargo-loaded or inhibitor-bound TgSORTLR","Cytosolic partners of the cytoplasmic tail not identified","Full cargo repertoire not defined"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["RHOPTRY PROTEINS (CARGO)","MICRONEME PROTEINS (CARGO)","CYTOSOLIC SORTING MACHINERY (VIA CYTOPLASMIC TAIL)"],"other_free_text":["Lumenal cargo-binding activity maps to Vps10, sortilin-C, and sortilin-M subdomains [#5].","Vps10 subdomain is the binding site for the small-molecule inhibitor AF38469, which blocks invasion, replication, and growth in vitro and in vivo [#6].","Ectopic lumenal domain acts as a dominant negative, mislocalizing endogenous receptor and cargo [#3].","Conditional loss abolishes rhoptry/microneme biogenesis, motility, invasion, and egress [#4]."]},"strain_conflicts":[]},"prefetch_data":{},"corpus_meta":[{"pmid":"22607804","id":"PMC_22607804","title":"Toxoplasma sortilin-like receptor regulates protein transport and is essential for apical secretory organelle biogenesis and host infection.","date":"2012","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/22607804","citation_count":108,"is_preprint":false},{"pmid":"38439083","id":"PMC_38439083","title":"Toxoplasma sortilin interacts with secretory proteins and it is critical for parasite proliferation.","date":"2024","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/38439083","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3425,"output_tokens":1544,"usd":0.016717,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6724,"output_tokens":2478,"usd":0.047785,"stage2_stop_reason":"end_turn"},"total_usd":0.064502,"stage1_batch_id":"msgbatch_015xmQKDRqnTh9anE4m7LiD6","stage2_batch_id":"msgbatch_01JLpkFTVhoQBNgqHCKFrVVU","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"TgSORTLR is a transmembrane protein that resides within Golgi-endosomal related compartments in Toxoplasma gondii.\",\n      \"method\": \"Subcellular fractionation and localization experiments\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiment with functional consequence, 108 citations, multiple orthogonal methods in one study\",\n      \"pmids\": [\"22607804\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The lumenal domain of TgSORTLR specifically interacts with rhoptry and microneme proteins, establishing it as a cargo receptor for apical secretory organelle proteins.\",\n      \"method\": \"Co-immunoprecipitation / binding interaction assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, functionally validated by dominant-negative and conditional ablation experiments, multiple orthogonal methods\",\n      \"pmids\": [\"22607804\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The cytoplasmic tail of TgSORTLR recruits cytosolic sorting machinery involved in both anterograde and retrograde protein transport.\",\n      \"method\": \"Protein interaction assays / domain dissection\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction demonstrated in single study, but mechanism of recruitment not fully resolved at atomic level from abstract\",\n      \"pmids\": [\"22607804\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ectopic expression of the N-terminal TgSORTLR lumenal domain acts as a dominant negative, causing mislocalization of both endogenous TgSORTLR and rhoptry/microneme proteins, confirming the lumenal domain mediates cargo capture.\",\n      \"method\": \"Dominant-negative overexpression with immunofluorescence readout\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative experiment with defined molecular phenotype, part of multi-method study with 108 citations\",\n      \"pmids\": [\"22607804\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Conditional ablation of TgSORTLR disrupts rhoptry and microneme biogenesis, inhibits parasite motility, and blocks both invasion into and egress from host cells, demonstrating TgSORTLR is essential for apical organelle formation and host infection.\",\n      \"method\": \"Conditional knockdown / genetic ablation with phenotypic readouts (organelle morphology, motility, invasion, egress assays)\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional loss-of-function with multiple specific cellular phenotypes, rigorously controlled, 108 citations\",\n      \"pmids\": [\"22607804\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The Vps10, sortilin-C, and sortilin-M subdomains of TgSORTLR are the binding regions for intracellular cargo protein transport, as determined by bio-layer interferometry with individual domain constructs.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, bio-layer interferometry with domain constructs\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay (bio-layer interferometry) with domain dissection, single lab, limited replication\",\n      \"pmids\": [\"38439083\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The small-molecule inhibitor AF38469 binds to the Vps10 subdomain of TgSORTLR and inhibits parasite invasion, replication, and intracellular growth in vitro and in a mouse infection model.\",\n      \"method\": \"Bio-layer interferometry (binding site determination), in vitro invasion/replication assays, mouse infection model\",\n      \"journal\": \"Parasites & vectors\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding site identified and functional inhibition demonstrated in vitro and in vivo, single lab study\",\n      \"pmids\": [\"38439083\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"TgSORTLR is a transmembrane receptor residing in Golgi-endosomal compartments whose lumenal Vps10, sortilin-C, and sortilin-M subdomains capture rhoptry and microneme cargo proteins for anterograde trafficking, while its cytoplasmic tail recruits cytosolic sorting machinery for retrograde transport, and conditional loss of TgSORTLR abolishes apical organelle biogenesis, parasite motility, and host cell invasion/egress.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TgSORTLR is a transmembrane cargo receptor of the Golgi-endosomal system in Toxoplasma gondii that governs biogenesis of the apical secretory organelles required for host infection [#0, #4]. Its lumenal domain captures rhoptry and microneme proteins for anterograde delivery, a cargo-binding function localized to the Vps10, sortilin-C, and sortilin-M subdomains [#1, #5], while its cytoplasmic tail recruits cytosolic sorting machinery for anterograde and retrograde transport [#2]. Ectopic expression of the lumenal domain acts as a dominant negative, mislocalizing both endogenous TgSORTLR and its rhoptry/microneme cargo [#3], and conditional ablation disrupts rhoptry and microneme biogenesis and abolishes parasite motility, host cell invasion, and egress [#4], establishing TgSORTLR as essential for infection. The Vps10 subdomain is druggable: the small molecule AF38469 binds it and inhibits invasion, replication, and intracellular growth in vitro and in a mouse infection model [#6]. Beyond these findings, the atomic-level mechanism of cytosolic machinery recruitment and the full cargo repertoire have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing where TgSORTLR resides and what it binds answered whether Toxoplasma uses a dedicated receptor to sort apical organelle cargo, defining it as a cargo receptor in the secretory pathway.\",\n      \"evidence\": \"Subcellular fractionation/localization plus co-immunoprecipitation binding assays in T. gondii\",\n      \"pmids\": [\"22607804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cargo repertoire beyond rhoptry/microneme proteins not enumerated\", \"Kinetics and affinity of cargo binding not quantified in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Domain dissection tested which part of the receptor performs each trafficking task, showing the lumenal domain captures cargo while the cytoplasmic tail engages cytosolic sorting machinery for bidirectional transport.\",\n      \"evidence\": \"Protein interaction assays and domain dissection; dominant-negative overexpression with immunofluorescence readout in T. gondii\",\n      \"pmids\": [\"22607804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cytosolic sorting adaptors recruited by the tail not resolved\", \"Atomic-level basis of tail-machinery interaction unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Conditional ablation tested whether TgSORTLR is functionally required, demonstrating it is essential for apical organelle biogenesis and the motility-dependent invasion/egress cycle.\",\n      \"evidence\": \"Conditional knockdown/genetic ablation with organelle morphology, motility, invasion, and egress assays in T. gondii\",\n      \"pmids\": [\"22607804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the invasion defect is solely secondary to organelle loss or also reflects direct trafficking roles not separated\", \"Effect on other secretory pathways not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapping cargo binding to specific lumenal subdomains refined the receptor mechanism and identified a druggable pocket, converting mechanistic knowledge into a therapeutic target.\",\n      \"evidence\": \"Immunoprecipitation, mass spectrometry, and bio-layer interferometry with individual domain constructs; AF38469 binding, in vitro invasion/replication assays, and mouse infection model in T. gondii\",\n      \"pmids\": [\"38439083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study with limited replication\", \"Structural basis of AF38469-Vps10 binding not resolved at atomic level\", \"Selectivity of AF38469 for parasite versus host sortilin not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the cytosolic sorting adaptors recruited by the TgSORTLR tail and the structural basis of cargo and inhibitor binding remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of cargo-loaded or inhibitor-bound TgSORTLR\", \"Cytosolic partners of the cytoplasmic tail not identified\", \"Full cargo repertoire not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 3, 5], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [1, 2, 5], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [0], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006886\", \"supporting_discovery_ids\": [1, 2, 4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0045324\", \"supporting_discovery_ids\": [4], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]},\n      {\"term_id\": \"GO:0006898\", \"supporting_discovery_ids\": [2], \"attribution\": [{\"species\": \"Toxoplasma gondii\", \"strain\": \"\"}]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"Rhoptry proteins (cargo)\",\n      \"Microneme proteins (cargo)\",\n      \"Cytosolic sorting machinery (via cytoplasmic tail)\"\n    ],\n    \"other_free_text\": [\n      \"Lumenal cargo-binding activity maps to Vps10, sortilin-C, and sortilin-M subdomains [#5].\",\n      \"Vps10 subdomain is the binding site for the small-molecule inhibitor AF38469, which blocks invasion, replication, and growth in vitro and in vivo [#6].\",\n      \"Ectopic lumenal domain acts as a dominant negative, mislocalizing endogenous receptor and cargo [#3].\",\n      \"Conditional loss abolishes rhoptry/microneme biogenesis, motility, invasion, and egress [#4].\"\n    ]\n  },\n  \"strain_conflicts\": []\n}\n```","audit_flag":null,"strains":[{"strain":"ME49","gene_id":"TGME49_290160","name":"SORTLR","product":"sortilin-like receptor SORTLR","uniprot_acc":"S8F3E1","chromosome":"TGME49_chrIX","start_pos":3601639},{"strain":"GT1","gene_id":"TGGT1_290160","name":null,"product":"putative sortilin","uniprot_acc":null,"chromosome":"TGGT1_chrIX","start_pos":3410442},{"strain":"RH88","gene_id":"TGRH88_014830","name":null,"product":"putative sortilin","uniprot_acc":null,"chromosome":"CM023090","start_pos":3666277},{"strain":"VEG","gene_id":"TGVEG_290160","name":null,"product":"putative sortilin","uniprot_acc":"A0A125YTK3","chromosome":"TGVEG_chrIX","start_pos":3637455}]}