Mechanisms of splicing-dependent trans-synaptic adhesion by PTPδ-IL1RAPL1/IL-1RAcP for synaptic differentiation.

Atsushi Yamagata,Tomoko Shiroshima,Yusuke Sato,Shuya Fukai,Tomoyuki Yoshida,Hisashi Mori,Masayoshi Mishina,Takeshi Uemura,Asami Maeda,Sakurako Goto-Ito,Shiho Iwasawa-Okamoto

doi:10.1038/ncomms7926

Abstract

Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes'. Receptor protein tyrosine phosphatase δ (PTPδ) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Here, we report crystal structures of PTPδ in complex with IL1RAPL1 and IL-1RAcP. The first immunoglobulin-like (Ig) domain of IL1RAPL1 directly recognizes the first splice insert, which is critical for binding to IL1RAPL1. The second splice insert functions as an adjustable linker that positions the Ig2 and Ig3 domains of PTPδ for simultaneously interacting with the Ig1 domain of IL1RAPL1 or IL-1RAcP. We further identified the IL1RAPL1-specific interaction, which appears coupled to the first-splice-insert-mediated interaction. Our results thus reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPδ and IL1RAPL1/IL-1RAcP.

Highlights

Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes’
Synapse formation is triggered through transsynaptic interactions between selective pairs of pre- and postsynaptic adhesion molecules known as ‘synaptic organizers’ or ‘synaptogenic proteins’, many of which are associated with neurodevelopmental disorders such as intellectual disability and autism[1,2,3,4,5,6]
Together with structurebased mutational analyses by surface plasmon resonance (SPR) spectroscopy and synaptogenic assays, we reveal the structural basis of the splicing-dependent trans-synaptic adhesion by protein tyrosine phosphatase d (PTPd) and IL1RAPL1/IL-1RAcP for synaptic differentiation

Summary

Introduction

Synapse formation is triggered through trans-synaptic interaction between pairs of pre- and postsynaptic adhesion molecules, the specificity of which depends on splice inserts known as ‘splice-insert signaling codes’. Receptor protein tyrosine phosphatase d (PTPd) can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to interleukin-1 receptor accessory protein (IL-1RAcP) and IL-1RAcP-like-1 (IL1RAPL1) in a splicing-dependent manner. Our results reveal the decoding mechanism of splice-insert signaling codes for synaptic differentiation induced by trans-synaptic adhesion between PTPd and IL1RAPL1/IL-1RAcP. Presynaptic type-IIa RPTPs form trans-synaptic adhesion by binding to their cognate postsynaptic organizers through their ECDs for inducing synaptic differentiation of neurons. The meB insertion increases binding of the meA9-containing variant, whereas the meA6containing variant absolutely requires the combination with meB These findings indicate that information of synaptogenic postsynaptic ligands for the type-IIa RPTPs is encoded in their splice inserts. Together with structurebased mutational analyses by surface plasmon resonance (SPR) spectroscopy and synaptogenic assays, we reveal the structural basis of the splicing-dependent trans-synaptic adhesion by PTPd and IL1RAPL1/IL-1RAcP for synaptic differentiation

Methods

Results

Conclusion