Abstract
The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs) with latrophilins (LPHNs/ADGRLs) promotes excitatory synapse formation when LPHNs simultaneously interact with FLRTs. Insertion of a short alternatively-spliced region within TENs abolishes the TEN-LPHN interaction and switches TEN function to specify inhibitory synapses. How alternative-splicing regulates TEN-LPHN interaction remains unclear. Here, we report the 2.9 Å resolution cryo-EM structure of the TEN2-LPHN3 complex, and describe the trimeric TEN2-LPHN3-FLRT3 complex. The structure reveals that the N-terminal lectin domain of LPHN3 binds to the TEN2 barrel at a site far away from the alternatively spliced region. Alternative-splicing regulates the TEN2-LPHN3 interaction by hindering access to the LPHN-binding surface rather than altering it. Strikingly, mutagenesis of the LPHN-binding surface of TEN2 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 TENs and LPHNs regulates synapse specificity.
Highlights
The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs) with latrophilins (LPHNs/ADGRLs) promotes excitatory synapse formation when LPHNs simultaneously interact with fibronectin leucine rich repeat transmembrane proteins (FLRTs)
All three proteins eluted in the same fractions, indicating the formation of a trimeric TEN2/ LPHN3/FLRT3 complex (Fig. 2e). These results suggest that TEN2 and FLRT3, both ligands of LPHN3, can simultaneously bind to LPHN3 and form a trimeric complex in vitro, supporting the in vivo observations that coincident binding of both TEN2 and FLRT3 to LPHN3 is required for excitatory synapse formation[3]
Synaptic specificity is further regulated by alternative splicing of TEN2 because only the LPHN3-binding splice variant of TEN2 can induce excitatory synapses, but not the other variant that induces inhibitory synapses likely in a LPHN3-independent manner
Summary
The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs) with latrophilins (LPHNs/ADGRLs) promotes excitatory synapse formation when LPHNs simultaneously interact with FLRTs. Insertion of a short alternatively-spliced region within TENs abolishes the TEN-LPHN interaction and switches TEN function to specify inhibitory synapses. Mutagenesis of the LPHN-binding surface of TEN2 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 TENs and LPHNs regulates synapse specificity. Recent work suggested that combinatorial sets of trans-synaptic interactions between cell-adhesion molecules, including teneurins (TENs or ODZs) and latrophilins (LPHNs or ADGRLs), mediate synapse formation and regulate the exquisite specification of synapses, but the underlying molecular mechanisms remain largely unexplored[2,3]. The precise molecular mechanisms of neither excitatory nor inhibitory synapse formation are known
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