biostudies-literatureZhang XNIMH NIH HHS322-329https://www.ebi.ac.uk/biostudies/studies/S-EPMC11808628biostudies-literatureUnknown387(6731)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 Science (New York, N.Y.)Reconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes.PMC11808628R01 MH126929Zhang XSudhof TCChen XMatus DfalseReconstitution of synaptic junctions orchestrated by teneurin-latrophilin complexes.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 2025-01-01T00:00:00Z2025 Jan2025-04-04T11:57:01.795Z2025-04-04T11:57:01.795ZS-EPMC118086283981890310.1126/science.adq3586