Reconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes

• 成果类型: Article
• 署名作者: Zhang, Xuchen; Chen, Xudong; Matus, Daniel; Sudhof, Thomas C.
• 署名单位: Stanford University; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11381
• DOI: 10.1126/science.adq3586
• 发表日期: 2025-01-17
• 页码: 322-329
• 关键词: cell-cell adhesion; structural basis; ORGANIZATION; RECOGNITION; 10-m/odz; FAMILY; domain; form

摘要

Synapses are organized by trans-synaptic adhesion molecules that coordinate assembly of pre- and postsynaptic specializations, which, in turn, are composed of scaffolding proteins forming liquid-liquid phase-separated condensates. Presynaptic teneurins mediate excitatory synapse organization by binding to postsynaptic latrophilins; however, the mechanism of action of teneurins, driven by extracellular domains evolutionarily derived from bacterial toxins, remains unclear. In this work, we show that only the intracellular sequence, a dimerization sequence, and extracellular bacterial toxin-derived latrophilin-binding domains of Teneurin-3 are required for synapse organization, suggesting that teneurin-induced latrophilin clustering mediates synaptogenesis. Intracellular Teneurin-3 sequences capture liquid-liquid phase-separated presynaptic active zone scaffolds, enabling us to reconstitute an entire synaptic junction from purified proteins in which trans-synaptic teneurin-latrophilin complexes recruit phase-separated pre- and postsynaptic specializations.