Specific N‐glycans on SynCAM Ig proteins regulate synaptic adhesion and synapse development

Abstract

Neurons communicate at specialized cell junctions called synapses. The protein complexes that span the synaptic cleft not only hold synapses together but also guide synapse development. SynCAMs (Synaptic Cell Adhesion Molecules) are a family of four homo‐and heterophilic immunoglobulin (Ig) proteins that contribute to these trans‐synaptic interactions. SynCAM 1 first participates in axo‐dendritic contacts of pre‐ and postsynaptic neurons and SynCAM proteins then drive the formation of excitatory synapses. Interestingly, the site‐specific N‐glycosylation of SynCAMs is a novel mechanism to regulate synapse development. Our mass‐spectrometric, crystallographic, and functional analyses of SynCAM 1 and 2 demonstrate that they carry N‐glycans adjacent to and within the first Ig domain that provides their extracellular binding interface. The glycosylation of these two SynCAM family members serves different roles. While N‐glycans within the Ig1 binding interface of SynCAM 2 reduce its binding, glycosylation at the SynCAM 1 Ig1 domain promotes its adhesion. Consequently, the ability to N‐glycosylate SynCAM 1 increases its trans‐synaptic interactions and synapse‐inducing activity. Together, N‐glycans modulate the adhesive interactions and synapse‐organizing functions of SynCAMs. Our findings support the notion that glycosylation plays important roles in synaptic surface interactions.