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bioRxiv · 10.1101/2020.01.13.901090

Structure of the teneurin-latrophilin complex: Alternative splicing controls synapse specificity by a novel mechanism

Li, J.·Xie, Y.·Cornelius, S.·Jiang, X.·Kordon, S. P.·Sando, R.·Pan, M.·Leon, K.·Sudhof, T. C.·Zhao, M.·Arac, D.
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Abstract

The trans-synaptic interaction of the cell-adhesion molecules teneurins (Tenms) with latrophilins (Lphns) promotes excitatory synapse formation when Lphns simultaneously interact with FLRTs. Insertion of a short alternatively-spliced region within Tenms abolishes the Tenm-Lphn interaction and switches Tenm function to specify inhibitory synapses. How Tenms bind to Lphns in a manner regulated by alternative splicing remains unclear. Here, we report the high-resolution cryo-EM structure of the Tenm2-Lphn3 complex, and describe the trimeric Tenm2-Lphn3-FLRT3 complex. The structure reveals that the N-terminal lectin-like domain of Lphn3 binds to the Tenm2 barrel at a site far away from the alternatively-spliced region. Alternative-splicing regulates the Tenm2-Lphn3 interaction by hindering access to the Lphn-binding surface rather than altering it. Strikingly, mutagenesis of the Lphn-binding surface of Tenm2 abolishes the Lphn3 interaction and impairs excitatory but not inhibitory synapse formation. These results suggest that a multi-level coincident binding mechanism mediated by a cryptic adhesion complex between Tenms and Lphns regulates synapse specificity.

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Li, J., Xie, Y., Cornelius, S., Jiang, X., Kordon, S. P., Sando, R., Pan, M., Leon, K., Sudhof, T. C., Zhao, M., Arac, D.. 2020-01-14. Structure of the teneurin-latrophilin complex: Alternative splicing controls synapse specificity by a novel mechanism. https://doi.org/10.1101/2020.01.13.901090

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