The LGI1-ADAM22 complex organizes PSD93 clustering at the axon initial segment

Postsynaptic density protein 93 (PSD93, also known as DLG2) is a scaffold protein of the membrane-associated guanylate kinase family containing multiple PDZ domains. It assembles ion channels, receptors and signaling molecules at synaptic and axonal membranes, particularly at the axon initial segment (AIS). However, the mechanism underlying the clustering of PSD93 at the AIS remains unclear. Here, we show that the secreted protein LGI1 and its transmembrane receptor ADAM22 are localized at the AIS of forebrain neurons. Using genetic knockout mice, we demonstrate that LGI1 and ADAM22 are reciprocally required for their clustering at the AIS, and the LGI1-ADAM22 complex is required for the clustering of PSD93 at the AIS; ADAM22 recruits PSD93 to plasma membrane through its PDZ-binding motif. Together, these findings identify the LGI1-ADAM22 complex as a key organizer of PSD93 clustering at the AIS.