Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions

Abstract

The heterophilic synaptic adhesion molecules, neuroligins and neurexins, are essential for establishing and maintaining neuronal circuits by modulating the formation and maturation of synapses. The neuroligin-neurexin adhesion is Ca 2+ -dependent and regulated by alternative splicing. We report a 2.4Å structure of the complex between the mouse neuroligin-1 (NL1) cholinesterase-like domain and the mouse neurexin 1β (NX1β) LNS (laminins, neurexins, and sex hormone-binding globulin-like) domain. The structure reveals a delicate neuroligin-neurexin assembly mediated by a hydrophilic, Ca 2+ -mediated, and solvent-supplemented interface, rendering it capable of being modulated by alternative splicing and other regulatory factors. Thermodynamic data support a mechanism where splicing site B of NL1 acts by modulating a salt bridge at the edge of the NL1-NX1β interface. Mapping neuroligin mutations implicated in autism indicates most such mutations are structurally destabilizing, supporting deficient neuroligin biosynthesis and processing as a common cause for this brain disorder.

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

“…By simultaneous binding to postsynaptic density 95 (PSD95), Nlgns link the postsynaptic density and control ionotropic neurotransmitter receptors to the exocytotic machinery of the presynaptic terminals (El-Husseini et al 2000;Wittenmayer et al 2009). Remarkably, mutations in Nlgn3/4 are involved in autism spectrum disorders (ASDs) which have been shown to destabilize the Nrxns-Nlgns complexes (Arac et al 2007;Chen et al 2008). In addition, a retention of Nlgns in the endoplasmic reticulum as well as a decrease in its affinity for Nrxns have been associated with some of those mutations (Comoletti et al 2004;Zhang et al 2009), suggesting that impaired trafficking and protein binding properties of Nrxns-Nlgns might be related to the disease.…”

Unusually rapid evolution of Neuroligin-4 in mice

“…Functionally, the NL4*-specific sequence insertions do not appear to alter the properties of NL4*, as far as tested, and especially do not appear to alter neurexin binding, which is different from the alternatively spliced 9-aa sequence in splice site B of NL1 (18). However, mapping the insertions into the recently published crystal structures of rodent NL1 and human NL4 (19)(20)(21) suggests that the insertions are on surface-exposed loops and could possibly alter the binding of NL4* to as-yet-unidentified nonneurexin ligands. Screening for binding partners of NLs and testing the functions of mouse NL4* and of NL4 in other species will clarify these issues.…”

Transcellular Neuroligin-2 Interactions Enhance Insulin Secretion and Are Integral to Pancreatic β Cell Function

“…Although unlikely, it is nonetheless possible that NL-2 and NL-1 enhance insulin secretion through divergent mechanisms and that the effect of NL-2, unlike that of NL-1, is exerted through neurexin. NL-2, however, has the lowest binding affinity of the neuroligins for neurexins (37). The structural basis for this low binding affinity has been described previously (18,37,40).…”

“…Small, discrete mutations preventing the interaction of NL-2 with neurexins have not been described. In contrast, the structural basis of the interaction between NL-1 and the neurexins has been extensively characterized by mutational analysis and crystallography, and key individual NL-1 residues have been identified (18,37,38). The single amino acid substitution G500A involves one such residue and prevents NL-1-neurexin binding (18,37,38).…”

“…In contrast, the structural basis of the interaction between NL-1 and the neurexins has been extensively characterized by mutational analysis and crystallography, and key individual NL-1 residues have been identified (18,37,38). The single amino acid substitution G500A involves one such residue and prevents NL-1-neurexin binding (18,37,38). 4 Because of the high degrees of sequence homology and substantial functional overlap between NL-1 and NL-2, we reasoned that, like NL-2, NL-1 would probably also increase insulin secretion (29,32,39).…”