Structural basis of SALM5-induced PTPδ dimerization for synaptic differentiation

SALM5, a synaptic adhesion molecule implicated in autism, induces presynaptic differentiation through binding to the LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) that have been highlighted as presynaptic hubs for synapse formation. The mechanisms underlying SALM5/LAR-RPTP interaction remain unsolved. Here we report crystal structures of human SALM5 LRR-Ig alone and in complex with human PTPδ Ig1–3 (MeA−). Distinct from other LAR-RPTP ligands, SALM5 mainly exists as a dimer with LRR domains from two protomers packed in an antiparallel fashion. In the 2:2 heterotetrameric SALM5/PTPδ complex, a SALM5 dimer bridges two separate PTPδ molecules. Structure-guided mutations and heterologous synapse formation assays demonstrate that dimerization of SALM5 is prerequisite for its functionality in inducing synaptic differentiation. This study presents a structural template for the SALM family and reveals a mechanism for how a synaptic adhesion molecule directly induces cis-dimerization of LAR-RPTPs into higher-order signaling assembly.
Synaptic adhesion molecules mediate synaptic differentiation and formation. Here the authors present the structures of the synaptic adhesion molecule SALM5 alone and in complex with the LAR family receptor protein tyrosine phosphatase (LAR-RPTP) PTPδ, which reveals how SALM5 dimerization facilitates higher-order signaling assembly of LAR-RPTPs.