Synaptic adhesion molecule signaling is activated and organized by tyrosine phosphorylation-induced biomolecular condensate formation

Synaptic connections are essential for proper brain function. Special proteins called synaptic adhesion molecules help link nerve cells together. However, the exact process by which these molecules form and signal within cells remains unclear. In this study, researchers discovered that a C. elegans adhesive protein named SYG-1 has multiple tyrosine phosphorylation sites in its cytoplasmic region.

These phosphorylation points are crucial for initiating the formation of the presynaptic part of the synapse. The team found that two enzymes called SRC-1 and SRC-2 are equally responsible for phosphorylating SYG-1 and are therefore vital for assembling the presynapse. When SYG-1 molecules become phosphorylated, they tend to gather together in clusters within a larger pool of SYG-1.

These clusters act as signal centers, marking the location where the active zone of the presynapse is formed. In a test tube experiment, the researchers recreated SYG-1 clusters using proteins that interact with phosphorylated sites and another molecule called WSP-1. This setup demonstrated that a dynamic condensate - a tightly packed group of molecules - forms.

However, if the process of forming phosphotyrosine adapters and the condensate is halted during experiments in living creatures, SYG-1 clusters do not develop, the presynapse does not form correctly, and neurotransmission is impaired. The findings suggest that phosphorylation of certain synaptic adhesion molecules leads to the formation of condensate-like clusters, which in turn kick-start the process of presynapse creation.