Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis

Receptor protein tyrosine phosphatase sigma (RPTP sigma) regulates neuronal extension and acts as a presynaptic nexus for multiple protein and proteoglycan interactions during synaptogenesis. Unknown mechanisms govern the shift in RPTP sigma function, from outgrowth promotion to synaptic organization. Here, we report crystallographic, electron microscopic and small-angle X-ray scattering analyses, which reveal sufficient inter-domain flexibility in the RPTP sigma extracellular region for interaction with both cis (same cell) and trans (opposite cell) ligands. Crystal structures of RPTP sigma bound to its postsynaptic ligand TrkC detail an interaction surface partially overlapping the glycosaminoglycan-binding site. Accordingly, heparan sulphate and heparin oligomers compete with TrkC for RPTP sigma binding in vitro and disrupt TrkC-dependent synaptic differentiation in neuronal co-culture assays. We propose that transient RPTP sigma ectodomain emergence from the presynaptic proteoglycan layer allows capture by TrkC to form a trans-synaptic complex, the consequent reduction in RPTP sigma flexibility potentiating interactions with additional ligands to orchestrate excitatory synapse formation.