Weaker neuroligin 2–neurexin β1 interaction tethers membranes and recruits gephyrin at membrane junctions through clustering

TL;DR

This study shows how the weak interaction between neuroligin 2 and neurexin β1 helps form synapses by tethering membranes and recruiting key proteins.

Contribution

The paper reveals a dual role of the NL2-NRXβ1 interaction as both a mechanical tether and signaling receptor.

Findings

NL2 and NRXβ1 cluster at intercellular junctions and recruit gephyrin.

The weak NL2-NRXβ1 interaction tethers lipid membranes despite low affinity.

NL2 promotes synapse formation through an avidity effect despite low binding strength.

Abstract

Single-pass transmembrane proteins neuroligin (NL) and neurexin (NRX) constitute a pair of synaptic adhesion molecules that are essential for the formation of functional synapses. Binding affinities vary by ~1000-fold between combinations of NL and NRX subtypes, which contribute to chemical and spatial specificities. Among major NL-NRX subtypes, NL2 and NRXβ1 have the lowest affinity. Here, we report structures of NL2 in complex with NRXβ1 in several conformations, along with NL2 alone. We identify mechanisms underlying the modulation of NL-NRX affinities and how the weaker NL2-NRXβ1 interaction alone is capable of tethering lipid membranes. We further show that NL2 and NRXβ1 cluster at intercellular junctions and recruit the master postsynaptic scaffolding protein gephyrin, which further clusters neurotransmitter receptors. These findings suggest a dual role of the NL2-NRXβ1 interaction—both as mechanical tether and as signaling receptor—to ensure correct spatial and chemical coordination between two cells to generate functional synapses.

Despite low affinities to neurexin due to structural features, neuroligin 2 promotes synapse formation through avidity effect.

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