Latrophilins function as heterophilic cell-adhesion molecules by binding to teneurins: regulation by alternative splicing

• Published in: The Journal of biological chemistry Vol. 289; no. 1; pp. 387 - 402
• Main Authors: Boucard, Antony A, Maxeiner, Stephan, Südhof, Thomas C
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 03.01.2014
• Subjects: Alternative Splicing - physiology; Animals; Cell Adhesion - physiology; Drosophila melanogaster; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; HEK293 Cells; Humans; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology; Neurons - chemistry; Neurons - cytology; Neurons - metabolism; Protein Binding - physiology; Rats; Receptors, Peptide - chemistry; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; Synapses - chemistry; Synapses - genetics; Synapses - metabolism; Tenascin - chemistry; Tenascin - genetics; Tenascin - metabolism; α-Latrotoxin; Ligand-binding Protein; Synapse Formation; G Protein-coupled Receptors (GPCR); Neurexin; Alternative Splicing; FLRT3; Neurons; Teneurin; Cell Adhesion
• DOI: 10.1074/jbc.M113.504779
• ISSN: 1083-351X; 0021-9258

Latrophilin-1, -2, and -3 are adhesion-type G protein-coupled receptors that are auxiliary α-latrotoxin receptors, suggesting that they may have a synaptic function. Using pulldowns, we here identify teneurins, type II transmembrane proteins that are also candidate synaptic cell-adhesion molecules, as interactors for the lectin-like domain of latrophilins. We show that teneurin binds to latrophilins with nanomolar affinity and that this binding mediates cell adhesion, consistent with a role of teneurin binding to latrophilins in trans-synaptic interactions. All latrophilins are subject to alternative splicing at an N-terminal site; in latrophilin-1, this alternative splicing modulates teneurin binding but has no effect on binding of latrophilin-1 to another ligand, FLRT3. Addition to cultured neurons of soluble teneurin-binding fragments of latrophilin-1 decreased synapse density, suggesting that latrophilin binding to teneurin may directly or indirectly influence synapse formation and/or maintenance. These observations are potentially intriguing in view of the proposed role for Drosophila teneurins in determining synapse specificity. However, teneurins in Drosophila were suggested to act as homophilic cell-adhesion molecules, whereas our findings suggest a heterophilic interaction mechanism. Thus, we tested whether mammalian teneurins also are homophilic cell-adhesion molecules, in addition to binding to latrophilins as heterophilic cell-adhesion molecules. Strikingly, we find that although teneurins bind to each other in solution, homophilic teneurin-teneurin binding is unable to support stable cell adhesion, different from heterophilic teneurin-latrophilin binding. Thus, mammalian teneurins act as heterophilic cell-adhesion molecules that may be involved in trans-neuronal interaction processes such as synapse formation or maintenance.