Structural basis of SALM5-induced PTPδ dimerization for synaptic differentiation

Area of Science:

• Neuroscience
• Structural Biology
• Molecular Biology

Background:

• SALM5 is a synaptic adhesion molecule linked to autism.
• SALM5 influences presynaptic differentiation by interacting with LAR family receptor protein tyrosine phosphatases (LAR-RPTPs).
• The precise interaction mechanisms between SALM5 and LAR-RPTPs are not fully understood.

Purpose of the Study:

• To elucidate the structural basis of the SALM5 and PTPδ interaction.
• To understand how SALM5 binding induces presynaptic differentiation.
• To provide a structural template for the SALM family.

Main Methods:

• X-ray crystallography was used to determine the structures of human SALM5 LRR-Ig alone and in complex with human PTPδ Ig1-3.
• Structure-guided mutagenesis was performed.
• Heterologous synapse formation assays were utilized.

Main Results:

• SALM5 predominantly exists as an antiparallel dimer.
• A 2:2 heterotetrameric complex reveals that a SALM5 dimer bridges two PTPδ molecules.
• SALM5 dimerization is essential for its role in inducing synaptic differentiation.

Conclusions:

• This study reveals the dimeric nature of SALM5 and its mechanism for inducing LAR-RPTP cis-dimerization.
• The findings provide a structural framework for SALM family interactions and synaptic assembly.
• This work deepens the understanding of molecular mechanisms underlying synapse formation and potential links to autism.