Structural basis of SALM5-induced PTPδ dimerization for synaptic differentiation

Zhaohan Lin, Jianmei Liu, Huandi Ding, Fei Xu and Heli Liu ()
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Zhaohan Lin: Peking University Health Science Center
Jianmei Liu: Peking University Health Science Center
Huandi Ding: Peking University Health Science Center
Fei Xu: Peking University Health Science Center
Heli Liu: Peking University Health Science Center

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02414-2

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