SORTLR

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.

1. 2012 High

   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

   PMID:22607804

   Open questions at the time

   • Precise cargo repertoire beyond rhoptry/microneme proteins not enumerated
   • Kinetics and affinity of cargo binding not quantified in this study
2. 2012 High

   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

   PMID:22607804

   Open questions at the time

   • Identity of the cytosolic sorting adaptors recruited by the tail not resolved
   • Atomic-level basis of tail-machinery interaction unknown
3. 2012 High

   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

   PMID:22607804

   Open questions at the time

   • 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
4. 2024 Medium

   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

   PMID:38439083

   Open questions at the time

   • 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

• The identity of the cytosolic sorting adaptors recruited by the TgSORTLR tail and the structural basis of cargo and inhibitor binding remain unresolved.
• No structural model of cargo-loaded or inhibitor-bound TgSORTLR
• Cytosolic partners of the cytoplasmic tail not identified
• Full cargo repertoire not defined