{"gene":"PF3D7_1451800","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2014,"finding":"SORTLR (PF3D7_1451800) was localized to the Golgi apparatus of P. falciparum asexual intraerythrocytic stage parasites, suggesting it functions as a protein sorting receptor at the Golgi and that retromer may mediate its retrograde transport from the endosome back to the Golgi.","method":"Fluorescence microscopy localization; brefeldin A treatment to distinguish Golgi from ER; co-localization with retromer and Rab7 markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with functional inference, single lab, multiple markers used but no functional loss-of-function or interaction assay performed for SORTLR itself","pmids":["24587025"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"SORTLR (PF3D7_1451800) interacts with regions of the GPI-anchored rhoptry-associated membrane antigen (RAMA) that are sufficient to target a fluorescent reporter to the rhoptries, suggesting SORTLR acts as a transmembrane escorter for transport of rhoptry-destined cargo from the Golgi apparatus to the rhoptries.","method":"Co-immunoprecipitation / interaction assay between SORTLR and RAMA domains; fluorescent reporter targeting assay","journal":"mSphere","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction shown by pulldown/co-IP and reporter assay in a single lab, two complementary approaches but no mutagenesis or reconstitution","pmids":["29299530"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"Knockdown of SORTLR (PF3D7_1451800) in P. falciparum prevents formation of the inner membrane complex, abrogates generation of new merozoites, and disrupts protein trafficking to the rhoptries, micronemes, and dense granules, causing apical complex proteins to accumulate in the endoplasmic reticulum and the parasitophorous vacuole; protein export to the erythrocyte and constitutive secretory pathway transport remain functional.","method":"Conditional knockdown (decreased expression) of SORTLR followed by assessment of inner membrane complex formation, merozoite generation, and organelle-specific cargo trafficking by immunofluorescence","journal":"Cellular microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional knockdown with multiple specific phenotypic readouts (IMC, merozoite formation, rhoptry/microneme/dense granule trafficking) and negative controls (secretory pathway intact), single lab but orthogonal phenotypic assays","pmids":["29582546"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"finding":"AP-1 adaptor complex acts through SORTLR (PF3D7_1451800) as a multi-ligand receptor in P. falciparum; AP-1 is required for intracellular growth, biogenesis of specialized invasion organelles, and formation of invasive progeny, and this activity is mediated via SORTLR.","method":"Genetic knockdown/disruption of AP-1 combined with proximity proteomics (proxiomes) from live cells; epistasis between AP-1 and SORTLR established by functional assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis and proximity proteomics in live cells, single lab, mechanistic link between AP-1 and SORTLR established but detail of the interaction mechanism is limited in the abstract","pmids":["41082687"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"SORTLR (PF3D7_1451800) is a transmembrane sortilin-family receptor that localizes to the Golgi apparatus of P. falciparum, where it acts as a multi-ligand escorter for cargo destined to the rhoptries, micronemes, and dense granules; it interacts physically with the rhoptry cargo RAMA, functions downstream of the AP-1 adaptor complex, is subject to retromer-mediated retrograde retrieval from endosomes to the Golgi, and is essential for inner membrane complex formation and merozoite biogenesis."},"narrative":{"mechanistic_narrative":"SORTLR (PF3D7_1451800) is a Golgi-localized sortilin-family sorting receptor of Plasmodium falciparum that governs delivery of cargo to the apical secretory organelles required for merozoite invasion [PMID:24587025, PMID:29582546]. Positioned at the Golgi apparatus, SORTLR acts as a transmembrane escorter that physically engages rhoptry-destined cargo, interacting with regions of the GPI-anchored rhoptry-associated membrane antigen (RAMA) that are themselves sufficient to direct a reporter to the rhoptries [PMID:29299530]. Its trafficking function is essential: conditional knockdown blocks formation of the inner membrane complex, abolishes production of new merozoites, and mislocalizes rhoptry, microneme, and dense granule cargo, which instead accumulate in the endoplasmic reticulum and parasitophorous vacuole, while protein export to the erythrocyte and the constitutive secretory pathway remain intact [PMID:29582546]. SORTLR operates downstream of the AP-1 adaptor complex, serving as the multi-ligand receptor through which AP-1 supports invasion-organelle biogenesis and formation of invasive progeny [PMID:41082687]. Localization data are also consistent with retromer-mediated retrograde retrieval of SORTLR from endosomes back to the Golgi [PMID:24587025].","teleology":[{"year":2014,"claim":"Establishing where SORTLR resides was the first step toward assigning it a sorting function, since a Golgi receptor implies a role at the trafficking hub of the secretory pathway.","evidence":"Fluorescence microscopy with brefeldin A treatment and co-localization with retromer and Rab7 markers in P. falciparum asexual stages","pmids":["24587025"],"confidence":"Medium","gaps":["No loss-of-function or interaction assay performed for SORTLR itself","Retromer-mediated retrieval inferred from marker co-localization, not directly demonstrated"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Identifying a physical cargo ligand converted the inferred sorting role into a defined receptor-cargo relationship, showing SORTLR escorts rhoptry-destined proteins.","evidence":"Co-immunoprecipitation between SORTLR and RAMA domains plus a fluorescent reporter targeting assay in P. falciparum","pmids":["29299530"],"confidence":"Medium","gaps":["No mutagenesis to map the interacting residues","No reconstitution to prove sufficiency of the SORTLR-RAMA interaction for transport","Whether SORTLR binds other apical cargoes directly not resolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Conditional depletion demonstrated that SORTLR is not merely a sorting receptor but is essential for invasion-organelle biogenesis and merozoite formation, defining the specificity of its trafficking role.","evidence":"Conditional knockdown of SORTLR with immunofluorescence readouts of IMC formation, merozoite generation, and organelle-specific cargo trafficking in P. falciparum","pmids":["29582546"],"confidence":"High","gaps":["Molecular basis by which loss of SORTLR blocks IMC formation not defined","Full repertoire of mistrafficked cargoes not enumerated","Order of events (trafficking defect vs. organelle failure) not dissected"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2025,"claim":"Placing SORTLR downstream of the AP-1 adaptor complex situated it within an ordered trafficking module, identifying the upstream machinery that directs SORTLR-dependent cargo sorting.","evidence":"Genetic disruption of AP-1 with proximity proteomics from live cells and functional epistasis between AP-1 and SORTLR in P. falciparum","pmids":["41082687"],"confidence":"Medium","gaps":["Direct physical AP-1-SORTLR interaction mechanism not detailed","Sorting signals recognized on SORTLR by AP-1 unknown","Single lab, mechanistic detail limited in the report"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":null,"claim":"The structural basis of ligand recognition and the full ligand repertoire that SORTLR sorts to rhoptries, micronemes, and dense granules remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of SORTLR or its cargo-binding interface","Beyond RAMA, no other direct SORTLR ligand mapped","Mechanism linking SORTLR trafficking to IMC assembly unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["RAMA (RHOPTRY-ASSOCIATED MEMBRANE ANTIGEN) — DIRECT INTERACTOR [#1]","AP-1 ADAPTOR COMPLEX — ACTS UPSTREAM OF SORTLR [#3]","RETROMER — INFERRED RETROGRADE RETRIEVAL OF SORTLR [#0]"],"other_free_text":["SORTLR is essential for inner membrane complex formation and merozoite biogenesis; its knockdown mislocalizes apical cargo to the ER and parasitophorous vacuole while sparing the constitutive secretory pathway and erythrocyte export [#2].","Functions as a multi-ligand sorting receptor delivering cargo to rhoptries, micronemes, and dense granules [#1, #2, #3]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"24587025","id":"PMC_24587025","title":"Evidence for a Golgi-to-endosome protein sorting pathway in Plasmodium falciparum.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24587025","citation_count":40,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["sortilin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32197482","id":"PMC_32197482","title":"Antimalarial Peptide and Polyketide Natural Products from the Fijian Marine Cyanobacterium Moorea producens.","date":"2020","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/32197482","citation_count":30,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["sortilin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29582546","id":"PMC_29582546","title":"The malaria parasite Plasmodium falciparum Sortilin is essential for merozoite formation and apical complex biogenesis.","date":"2018","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29582546","citation_count":29,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["sortilin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"29299530","id":"PMC_29299530","title":"Evidence that the Plasmodium falciparum Protein Sortilin Potentially Acts as an Escorter for the Trafficking of the Rhoptry-Associated Membrane Antigen to the Rhoptries.","date":"2018","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/29299530","citation_count":25,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["sortilin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"41082687","id":"PMC_41082687","title":"Vesicle adaptors in malaria parasites show conservation and flexibility of protein sorting machinery.","date":"2025","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/41082687","citation_count":2,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["sortilin"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36936758","id":"PMC_36936758","title":"An image-based high-content screening for compounds targeting Toxoplasma gondii repurposed inhibitors effective against the malaria parasite Plasmodium falciparum.","date":"2023","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36936758","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["sortilin"],"competing_organism_flag":true,"competing_organism_match":"Toxoplasma","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5660,"output_tokens":1278,"usd":0.018075,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6186,"output_tokens":2415,"usd":0.045652,"stage2_stop_reason":"end_turn"},"total_usd":0.063727,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"SORTLR (PF3D7_1451800) was localized to the Golgi apparatus of P. falciparum asexual intraerythrocytic stage parasites, suggesting it functions as a protein sorting receptor at the Golgi and that retromer may mediate its retrograde transport from the endosome back to the Golgi.\",\n      \"method\": \"Fluorescence microscopy localization; brefeldin A treatment to distinguish Golgi from ER; co-localization with retromer and Rab7 markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with functional inference, single lab, multiple markers used but no functional loss-of-function or interaction assay performed for SORTLR itself\",\n      \"pmids\": [\"24587025\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SORTLR (PF3D7_1451800) interacts with regions of the GPI-anchored rhoptry-associated membrane antigen (RAMA) that are sufficient to target a fluorescent reporter to the rhoptries, suggesting SORTLR acts as a transmembrane escorter for transport of rhoptry-destined cargo from the Golgi apparatus to the rhoptries.\",\n      \"method\": \"Co-immunoprecipitation / interaction assay between SORTLR and RAMA domains; fluorescent reporter targeting assay\",\n      \"journal\": \"mSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction shown by pulldown/co-IP and reporter assay in a single lab, two complementary approaches but no mutagenesis or reconstitution\",\n      \"pmids\": [\"29299530\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of SORTLR (PF3D7_1451800) in P. falciparum prevents formation of the inner membrane complex, abrogates generation of new merozoites, and disrupts protein trafficking to the rhoptries, micronemes, and dense granules, causing apical complex proteins to accumulate in the endoplasmic reticulum and the parasitophorous vacuole; protein export to the erythrocyte and constitutive secretory pathway transport remain functional.\",\n      \"method\": \"Conditional knockdown (decreased expression) of SORTLR followed by assessment of inner membrane complex formation, merozoite generation, and organelle-specific cargo trafficking by immunofluorescence\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional knockdown with multiple specific phenotypic readouts (IMC, merozoite formation, rhoptry/microneme/dense granule trafficking) and negative controls (secretory pathway intact), single lab but orthogonal phenotypic assays\",\n      \"pmids\": [\"29582546\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AP-1 adaptor complex acts through SORTLR (PF3D7_1451800) as a multi-ligand receptor in P. falciparum; AP-1 is required for intracellular growth, biogenesis of specialized invasion organelles, and formation of invasive progeny, and this activity is mediated via SORTLR.\",\n      \"method\": \"Genetic knockdown/disruption of AP-1 combined with proximity proteomics (proxiomes) from live cells; epistasis between AP-1 and SORTLR established by functional assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis and proximity proteomics in live cells, single lab, mechanistic link between AP-1 and SORTLR established but detail of the interaction mechanism is limited in the abstract\",\n      \"pmids\": [\"41082687\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"SORTLR (PF3D7_1451800) is a transmembrane sortilin-family receptor that localizes to the Golgi apparatus of P. falciparum, where it acts as a multi-ligand escorter for cargo destined to the rhoptries, micronemes, and dense granules; it interacts physically with the rhoptry cargo RAMA, functions downstream of the AP-1 adaptor complex, is subject to retromer-mediated retrograde retrieval from endosomes to the Golgi, and is essential for inner membrane complex formation and merozoite biogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SORTLR (PF3D7_1451800) is a Golgi-localized sortilin-family sorting receptor of Plasmodium falciparum that governs delivery of cargo to the apical secretory organelles required for merozoite invasion [#0, #2]. Positioned at the Golgi apparatus, SORTLR acts as a transmembrane escorter that physically engages rhoptry-destined cargo, interacting with regions of the GPI-anchored rhoptry-associated membrane antigen (RAMA) that are themselves sufficient to direct a reporter to the rhoptries [#1]. Its trafficking function is essential: conditional knockdown blocks formation of the inner membrane complex, abolishes production of new merozoites, and mislocalizes rhoptry, microneme, and dense granule cargo, which instead accumulate in the endoplasmic reticulum and parasitophorous vacuole, while protein export to the erythrocyte and the constitutive secretory pathway remain intact [#2]. SORTLR operates downstream of the AP-1 adaptor complex, serving as the multi-ligand receptor through which AP-1 supports invasion-organelle biogenesis and formation of invasive progeny [#3]. Localization data are also consistent with retromer-mediated retrograde retrieval of SORTLR from endosomes back to the Golgi [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing where SORTLR resides was the first step toward assigning it a sorting function, since a Golgi receptor implies a role at the trafficking hub of the secretory pathway.\",\n      \"evidence\": \"Fluorescence microscopy with brefeldin A treatment and co-localization with retromer and Rab7 markers in P. falciparum asexual stages\",\n      \"pmids\": [\"24587025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No loss-of-function or interaction assay performed for SORTLR itself\", \"Retromer-mediated retrieval inferred from marker co-localization, not directly demonstrated\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying a physical cargo ligand converted the inferred sorting role into a defined receptor-cargo relationship, showing SORTLR escorts rhoptry-destined proteins.\",\n      \"evidence\": \"Co-immunoprecipitation between SORTLR and RAMA domains plus a fluorescent reporter targeting assay in P. falciparum\",\n      \"pmids\": [\"29299530\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis to map the interacting residues\", \"No reconstitution to prove sufficiency of the SORTLR-RAMA interaction for transport\", \"Whether SORTLR binds other apical cargoes directly not resolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional depletion demonstrated that SORTLR is not merely a sorting receptor but is essential for invasion-organelle biogenesis and merozoite formation, defining the specificity of its trafficking role.\",\n      \"evidence\": \"Conditional knockdown of SORTLR with immunofluorescence readouts of IMC formation, merozoite generation, and organelle-specific cargo trafficking in P. falciparum\",\n      \"pmids\": [\"29582546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis by which loss of SORTLR blocks IMC formation not defined\", \"Full repertoire of mistrafficked cargoes not enumerated\", \"Order of events (trafficking defect vs. organelle failure) not dissected\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing SORTLR downstream of the AP-1 adaptor complex situated it within an ordered trafficking module, identifying the upstream machinery that directs SORTLR-dependent cargo sorting.\",\n      \"evidence\": \"Genetic disruption of AP-1 with proximity proteomics from live cells and functional epistasis between AP-1 and SORTLR in P. falciparum\",\n      \"pmids\": [\"41082687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical AP-1-SORTLR interaction mechanism not detailed\", \"Sorting signals recognized on SORTLR by AP-1 unknown\", \"Single lab, mechanistic detail limited in the report\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of ligand recognition and the full ligand repertoire that SORTLR sorts to rhoptries, micronemes, and dense granules remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of SORTLR or its cargo-binding interface\", \"Beyond RAMA, no other direct SORTLR ligand mapped\", \"Mechanism linking SORTLR trafficking to IMC assembly unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016020\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006886\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0045176\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0042147\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RAMA (rhoptry-associated membrane antigen) — direct interactor [#1]\",\n      \"AP-1 adaptor complex — acts upstream of SORTLR [#3]\",\n      \"retromer — inferred retrograde retrieval of SORTLR [#0]\"\n    ],\n    \"other_free_text\": [\n      \"SORTLR is essential for inner membrane complex formation and merozoite biogenesis; its knockdown mislocalizes apical cargo to the ER and parasitophorous vacuole while sparing the constitutive secretory pathway and erythrocyte export [#2].\",\n      \"Functions as a multi-ligand sorting receptor delivering cargo to rhoptries, micronemes, and dense granules [#1, #2, #3].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1451800","name":null,"product":"sortilin","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1315500","name":null,"product":"sortilin, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1230300","name":null,"product":"sortilin, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"SORTLR","evaluation":null}