Abstract
Synapse formation is triggered by trans-synaptic interactions of cell adhesion molecules, termed synaptic organizers. Three members of type-II receptor protein tyrosine phosphatases (classified as type-IIa RPTPs; PTPδ, PTPσ and LAR) are known as presynaptic organizers. Synaptic adhesion-like molecules (SALMs) have recently emerged as a family of postsynaptic organizers. Although all five SALM isoforms can bind to the type-IIa RPTPs, only SALM3 and SALM5 reportedly have synaptogenic activities depending on their binding. Here, we report the crystal structures of apo-SALM5, and PTPδ–SALM2 and PTPδ–SALM5 complexes. The leucine-rich repeat (LRR) domains of SALMs interact with the second immunoglobulin-like (Ig) domain of PTPδ, whereas the Ig domains of SALMs interact with both the second and third Ig domains of PTPδ. Unexpectedly, the structures exhibit the LRR-mediated 2:2 complex. Our synaptogenic co-culture assay using site-directed SALM5 mutants demonstrates that presynaptic differentiation induced by PTPδ–SALM5 requires the dimeric property of SALM5.
Highlights
Synapse formation is triggered by trans-synaptic interactions of cell adhesion molecules, termed synaptic organizers
The electron densities of the Ig domains of SALM2 and SALM5 became relatively clear upon binding to PTPδ, suggesting that the Ig domains of SALM2 and SALM5 were partly stabilized by the interaction with PTPδ
The PTPδ residues involved in the binding to SALM2 and SALM5 are completely conserved among the type-IIa receptor protein tyrosine phosphatases (RPTPs) (Supplementary Fig. 6)
Summary
Synapse formation is triggered by trans-synaptic interactions of cell adhesion molecules, termed synaptic organizers. The type-IIa RPTPs have three members, PTPδ, PTPσ, and LAR These members possess a large extracellular domain (ECD) consisting of three immunoglobulin-like (Ig) domains and four to eight fibronectin type-III (Fn) domains, followed by a single transmembrane helix and a cytoplasmic domain harboring two protein tyrosine phosphatase (PTP) domains (Fig. 1a): the first PTP domain is active, while the second domain is inactive. Synaptic adhesion-like molecules (SALMs; known as Lrfns) family proteins have recently emerged as a family of postsynaptic organizers that bind to the type-IIa RPTPs18–20. SALM family proteins have five isoforms (SALM1–SALM5) Their ECDs share the same domain organization consisting of a leucine-rich repeat (LRR) domain, an Ig domain and an Fn domain with 35% amino-acid sequence identity (Fig. 1a). Despite the functional importance of trans-synaptic adhesions mediated by SALMs and the type-IIa RPTPs in neuronal development, their underlying structural mechanisms remain elusive. Together with structure-based mutagenesis, in vitro binding analysis with surface-plasmon resonance (SPR) spectroscopy and synaptogenic co-culture assay, we reveal the structural basis of trans-synaptic interactions between the SALMs and type-IIa RPTPs
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