Structural basis for LAR-RPTP/Slitrk complex-mediated synaptic adhesion

Abstract

Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit-and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structureguided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

“…All cell biological assays were performed as described (27,41). Generation of lentiviral shRNA plasmids, production, and characterization of recombinant lentiviruses were performed as described (42) and are detailed in SI Methods.…”

The balancing act of GABAergic synapse organizers

“…Intriguingly, both Slitrk3 and PTPd have been implicated in obsessive-compulsive disorder (OCD) [38]. A co-crystal structure of the Slitrk1/PTPd complex has allowed analysis of the discrete molecular steps that drive Slitrk-mediated presynaptic differentiation [39]. Slitrk3 transgenic mice in which the interaction with PTPd is specifically perturbed might trigger an imbalance the E/I ratio; if so, this model could provide new insights into the pathophysiological mechanisms underlying neuropsychiatric disorders such as OCD.…”

Transcellular Nanoalignment of Synaptic Function

“…The assembly of trans-synaptic nanocolumns could include the lateral oligomerization of cleft components (Dean et al, 2003; Fogel et al, 2011; Um et al, 2014), bridging molecules (Singh et al, 2016; Yuzaki, 2017), or be regulated by steric hindrance to block interactions, such as the ones shown for neuroligins (Gangwar et al, 2017; Kim et al, 2017; Elegheert et al, 2017). In addition to these direct interactions, molecular crowding within the tightly packed environment of synaptic specializations needs to be considered as a factor in placing nanocolumns (Li et al, 2016).…”