Postsynaptic density-93 (PSD93) is a membrane-associated guanylate kinase (MAGUK) family scaffolding protein 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 LGI1- ADAM22 complex are 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.
Zhang et al. (Wed,) studied this question.