Leucine-rich glioma inactivated 1 (LGI1) is a ganglioside-binding protein

In Lgi1^-/- mice, increased neuronal excitability is accompanied by a marked decrease in Kv1 channels, but the mechanism linking LGI1 loss to reduced ion channel expression remains unknown. We show that LGI1 contains multiple conserved canonical ganglioside-binding domains (GBDs) and that GT1b copurifies with LGI1 antibodies from native rat brain extracts. Recombinant LGI1 bound ganglioside-containing liposomes, and the ganglioside-binding capacity of surface-exposed GBD peptide sequences was confirmed experimentally. These findings suggest LGI1 interacts with gangliosides and may help organize lipid membrane platforms that accommodate functional protein complexes. We hypothesize that loss of LGI1 destabilizes these platforms, contributing to the reduced ion channel expression observed in Lgi1^-/- mice.