Abstract
Synapse formation is induced by transsynaptic interaction of neuronal cell-adhesion molecules termed synaptic organizers. Type IIa receptor protein tyrosine phosphatases (IIa RPTPs) function as presynaptic organizers. The cytoplasmic domain of IIa RPTPs consists of two phosphatase domains, and the membrane-distal one (D2) is essential for synapse formation. Liprin-α, which is an active zone protein critical for synapse formation, interacts with D2 via its C-terminal domain composed of three tandem sterile alpha motifs (tSAM). Structural mechanisms of this critical interaction for synapse formation remain elusive. Here, we report the crystal structure of the complex between mouse PTPδ D2 and Liprin-α3 tSAM at 1.91 Å resolution. PTPδ D2 interacts with the N-terminal helix and the first and second SAMs (SAM1 and SAM2, respectively) of Liprin-α3. Structure-based mutational analyses in vitro and in cellulo demonstrate that the interactions with Liprin-α SAM1 and SAM2 are essential for the binding and synaptogenic activity.
Highlights
Synapse formation is induced by transsynaptic interaction of neuronal cell-adhesion molecules termed synaptic organizers
The structural mechanism for the interaction between PTPδ D2 and Liprin-α3 tandem sterile alpha motifs (tSAM), which we revealed in this study, confirms the specific binding between the D2 domain of IIa RPTPs and the tSAM domain of Liprin-α proteins
We examined the effects of the PTPδ mutations that impair the interaction with either or both SAM1 and SAM2 domains of Liprin-α on presynaptic differentiation
Summary
Synapse formation is induced by transsynaptic interaction of neuronal cell-adhesion molecules termed synaptic organizers. Liprin-α, which is an active zone protein critical for synapse formation, interacts with D2 via its C-terminal domain composed of three tandem sterile alpha motifs (tSAM). The extracellular domain mediates a heterophilic, transsynaptic interaction with various postsynaptic organizers such as Netrin-G ligand 3 (NGL-3)[6,7], Tropomyosin kinase C (TrkC)[8], Interleukin-1 receptor accessory protein-like 1 (IL1RAPL1)[9], Interleukin-1 receptor accessory protein (IL-1RAcP)[10], Slit- and Trk-like family protein (Slitrk) 1–Slitrk[611,12], synaptic adhesion-like molecule (SALM) 313, and SALM514. All of these postsynaptic organizers except NGL-3 interact with the Ig domains of IIa RPTPs15–20. Liprin-α2 regulates the turnover of the active zone proteins, calcium/calmodulin-dependent serine kinase (CASK) and RIM1/2, to facilitate synaptic transmission[37]
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