Structural basis of trans-synaptic interactions between PTPδ and SALMs for inducing synapse formation

Synapse formation is triggered by trans-synaptic interactions of cell adhesion molecules, termed synaptic organizers. Three members of type-II receptor protein tyrosine phosphatases (classified as type-IIa RPTPs; PTP delta, PTPs and LAR) are known as presynaptic organizers. Synaptic adhesion-like molecules (SALMs) have recently emerged as a family of postsynaptic organizers. Although all five SALM isoforms can bind to the type-IIa RPTPs, only SALM3 and SALM5 reportedly have synaptogenic activities depending on their binding. Here, we report the crystal structures of apo-SALM5, and PTP delta-SALM2 and PTP delta-SALM5 complexes. The leucine-rich repeat (LRR) domains of SALMs interact with the second immunoglobulin-like (Ig) domain of PTP delta, whereas the Ig domains of SALMs interact with both the second and third Ig domains of PTP delta. Unexpectedly, the structures exhibit the LRRmediated 2: 2 complex. Our synaptogenic co-culture assay using site-directed SALM5 mutants demonstrates that presynaptic differentiation induced by PTP delta-SALM5 requires the dimeric property of SALM5.