Structural insights into selective interaction between type IIa receptor protein tyrosine phosphatases and Liprin-α

Area of Science:

• Neuroscience
• Molecular Biology
• Structural Biology

Background:

• Synapse formation is mediated by transsynaptic interactions of neuronal cell-adhesion molecules called synaptic organizers.
• Type IIa receptor protein tyrosine phosphatases (IIa RPTPs) act as presynaptic organizers, with their D2 cytoplasmic domain being essential for synapse formation.
• Liprin-α, an active zone protein, interacts with the D2 domain via its C-terminal tandem sterile alpha motifs (tSAM).

Purpose of the Study:

• To elucidate the structural mechanisms underlying the interaction between the PTPδ D2 domain and Liprin-α tSAM, which is critical for synapse formation.
• To understand how this interaction contributes to the synaptogenic activity of presynaptic organizers.

Main Methods:

• Crystallography to determine the structure of the mouse PTPδ D2 and Liprin-α3 tSAM complex at 1.91 Å resolution.
• Structure-based mutational analyses were performed both in vitro and in cellulo.

Main Results:

• The crystal structure revealed that PTPδ D2 interacts with the N-terminal helix and the first two SAMs (SAM1 and SAM2) of Liprin-α3.
• Mutational analyses confirmed that interactions with Liprin-α SAM1 and SAM2 are indispensable for binding.
• These interactions were also shown to be essential for the synaptogenic activity of the complex.

Conclusions:

• The study provides the first structural insights into the interaction between a presynaptic organizer (PTPδ D2) and an active zone protein (Liprin-α tSAM).
• The findings highlight the critical role of Liprin-α SAM1 and SAM2 in mediating this interaction and its importance for synapse formation.
• This work lays the foundation for further investigations into the molecular mechanisms of synaptic development.