Trans-synaptic Adhesions between Netrin-G Ligand-3 (NGL-3) and Receptor Tyrosine Phosphatases LAR, Protein-tyrosine Phosphatase δ (PTPδ), and PTPσ via Specific Domains Regulate Excitatory Synapse Formation

Kwon, Seok-Kyu; Woo, Jooyeon; Kim, Soo Young; Kim, Hyun; Kim, Eunjoon

doi:10.1074/jbc.m109.061127

Cited by 149 publications

(180 citation statements)

References 75 publications

(87 reference statements)

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“…1). NGL-3 bound to the FNIII repeats but not to Ig1-3, which is consistent with a previous report that NGL-3 binds to the first two FNIII repeats of LARRPTPs 14 .…”

Section: Minimal Domain Identification For Binding and Synaptogenesissupporting

confidence: 81%

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

et al. 2014

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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.

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“…1). NGL-3 bound to the FNIII repeats but not to Ig1-3, which is consistent with a previous report that NGL-3 binds to the first two FNIII repeats of LARRPTPs 14 .…”

Section: Minimal Domain Identification For Binding and Synaptogenesissupporting

confidence: 81%

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

et al. 2014

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“…This may be a fundamental principle underlying neuroligin physiology with ramifications even outside the central nervous system; in fact, a recent study found that clustered neuroligin stimulates transcellular insulin release from pancreatic β cells (acting through an unknown partner other than neurexin), whereas diffuse neuroligin does not (27). Within the CNS, neuroligins are only one class of what is an emerging superfamily of postsynaptic neurexin ligands, including LRRTMs (6-8), cerebellins (9), and the G-protein-coupled receptor latrophilin-1 (28), which, together with neurexin, are situated within an even larger class of synaptic adhesion complexes, including those formed by cadherins (29), the synaptic cell adhesion molecule (SynCAM) family (30), netrin-G ligand-3 and receptor protein tyrosine phosphatases (31,32), and teneurins (33). Given the apparent mechanistic requirement of neurexin clustering for neuroligin-induced synaptogenesis, it will be of considerable interest to explore the extent to which this is a shared function among neurexin ligands and synaptic adhesion complexes in general.…”

Section: Discussionmentioning

confidence: 99%

Dimerization of postsynaptic neuroligin drives synaptic assembly via transsynaptic clustering of neurexin

Shipman

Nicoll²

2012

Proc. Natl. Acad. Sci. U.S.A.

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The transsynaptic complex of neuroligin (NLGN) and neurexin forms a physical connection between pre-and postsynaptic neurons that occurs early in the course of new synapse assembly. Both neuroligin and neurexin have, indeed, been proposed to exhibit active, instructive roles in the formation of synapses. However, the process by which these instructive roles play out during synaptogenesis is not well understood. Here, we examine one aspect of postsynaptic neuroligin with regard to its synaptogenic properties: its basal state as a constitutive dimer. We show that dimerization is required for the synaptogenic properties of neuroligin and likely serves to induce presynaptic differentiation via a transsynaptic clustering of neurexin. Further, we introduce chemically inducible, exogenous dimerization domains to the neuroligin molecule, effectively bestowing chemical control of neuroligin dimerization. This allows us to identify the acute requirements of neuroligin dimerization by chemically manipulating the monomeric-to-dimeric conversion of neuroligin. Based on the results of the inducible dimerization experiments, we propose a model in which dimerized neuroligin induces the mechanical clustering of presynaptic molecules as part of a requisite step in the coordinated assembly of a chemical synapse.T he synapse is among the most complex of cellular structures, dense with highly organized protein interactions. Although our knowledge of this molecular matrix is expanding rapidly, the precise dynamics that govern the formation of a synapse, with its matched asymmetric sides, are still not fully understood. However, some particularly important interactions are beginning to emerge. For instance, the transsynaptic complex of presynaptic neurexin and postsynaptic neuroligin (NLGN) has been proposed to lie at the heart of an emerging synapse (1, 2).Independent manipulations of either neuroligin or neurexin can result in modifications of both pre-and postsynaptic assembly, suggesting an instructive transsynaptic role for the neuroligin/neurexin complex in synaptic formation. Most strikingly, in experiments using a coculture system of neurons and nonneuronal cells, neuroligin expressed in nonneuronal cells is able to induce the formation of functional presynaptic terminals onto those cells from cocultured neurons (3), whereas neurexin expression in nonneuronal cells supports the formation of postsynaptic specializations at the junctions of those nonneuronal cells and cocultured neurons (4). Whether or not the neuroligin/neurexin complex is absolutely required for synapse formation is not clear, given that dissociated hippocampal and cortical cultures from triple-knockout mice lacking neuroligins 1, 2, and 3 display normal synapse density, although these mice do die at birth from respiratory failure as a consequence of reduced synaptic transmission in the brainstem (5). Whereas this finding certainly suggests that the neuroligin family is not essential for synaptic formation, it remains possible that compensation by another fami...

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“…This aspect of SALM5 function thus seems to distinguish SALM5 from neuroligins, which act specifically on either excitatory or inhibitory synapses, although further studies on SALM5 are required to confirm this. In addition, LRRTM2 and NGL-3, which contain LRRs similar to SALMs, have been implicated mainly in the regulation of excitatory synapse formation (de Wit et al, 2009;Ko et al, 2009;Linhoff et al, 2009;Woo et al, 2009b;Kwon et al, 2010).…”

Section: Involvement Of a Subset Of Salm Family Members In Presynaptimentioning

confidence: 99%

Selected SALM (Synaptic Adhesion-Like Molecule) Family Proteins Regulate Synapse Formation

Mah¹,

Ko²,

Nam³

et al. 2010

J. Neurosci.

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Synaptic cell adhesion molecules regulate various steps of synapse formation. Despite the great diversity of neuronal synapses, relatively few adhesion molecules with synaptogenic activity have been identified. Synaptic adhesion-like molecules (SALMs) are members of a family of cell adhesion molecules known to regulate neurite outgrowth and synapse maturation; however, the role of SALMs in synapse formation remains unknown. We found that expression of the SALM family proteins SALM3 and SALM5 in nonneural and neural cells induces both excitatory and inhibitory presynaptic differentiation in contacting axons. SALM3 and SALM5 proteins are enriched in synaptic fractions, and form strong (SALM3) or weak (SALM5) complexes with postsynaptic density-95 (PSD-95), an abundant postsynaptic scaffolding protein at excitatory synapses. Aggregation of SALM3, but not SALM5, on dendritic surfaces induces clustering of PSD-95. Knockdown of SALM5 reduces the number and function of excitatory and inhibitory synapses. These results suggest that selected SALM family proteins regulate synapse formation, and that SALM3 and SALM5 may promote synapse formation through distinct mechanisms.

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Trans-synaptic Adhesions between Netrin-G Ligand-3 (NGL-3) and Receptor Tyrosine Phosphatases LAR, Protein-tyrosine Phosphatase δ (PTPδ), and PTPσ via Specific Domains Regulate Excitatory Synapse Formation

Cited by 149 publications

References 75 publications

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

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

Dimerization of postsynaptic neuroligin drives synaptic assembly via transsynaptic clustering of neurexin

Selected SALM (Synaptic Adhesion-Like Molecule) Family Proteins Regulate Synapse Formation

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