SALM5, a synaptic adhesion molecule implicated in autism, induces presynaptic differentiation through binding to the LAR family receptor protein tyrosine phosphatases (LARRPTPs) 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. Structureguided 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.

Siglec-15, an inhibitory immune checkpoint, is an emerging target in cancer immunotherapy. Blocking the function of Siglec-15 is an excellent strategy for cancer treatment and antibody blockade has been used to target Siglec-15. However, whether Fc-mediated effector functions contribute to the therapeutic effect of antibodies remains unclear. Herein, we generated a monoclonal antibody, 1-15D1, which had a high binding affinity with Siglec-15 and strongly activated T-cell immune response in vitro. Subsequently, the Fc-mediated effector functions of 1-15D1 were explored in a Siglec-15 humanized mouse model, and further improvement in antitumor efficacy was observed in the mouse IgG2a isotype group. Thus, we demonstrate that the antitumor effects of 1-15D1 were mediated via multiple factors. In addition to the T-cell immune response, 2 novel mechanisms were explored, including the internalization of the cell surface Siglec-15 and Fc-mediated effector functions. In conclusion, our studies not only provide a potential agent for the improvement of cancer immunotherapy but also suggest that a specific role of Fc-mediated immune regulation may improve the therapeutic potency of Siglec-15 monoclonal antibody.