Structural basis for integration of GluD receptors within synaptic organizer complexes

Abstract

Ionotropic glutamate receptor family members (iGluRs) are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking post-synaptic iGluR δ2 (GluD2) and pre-synaptic β-neurexin-1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers “anchor” GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis, and is essential for D-Serine-dependent GluD2 signaling in vivo, underlying long-term depression of cerebellar parallel fiber-Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function.

Conformational Plasticity in the Transsynaptic Neurexin-Cerebellin-Glutamate Receptor Adhesion Complex

“…On the post-synaptic end of this complex, we present the first full-length dimeric ectodomain of a GluD, which shows a previously unobserved conformation of iGluR ectodomains, where the ligand-binding domains are “swung-out” in a fashion alike the desensitized state of iGluRs. Combined with the recently published structure of the GluD2-Cbln complex by Elegheert et al (2016), our results open the way for further studies on the regulation and signaling through this trans-synaptic complex.…”

“…The trans-synaptic complex made up of Nrxn, Cbln, and GluD allows for specificity to be established for PF-PC synapses, while the complex initiates signaling for synaptic differentiation presumably on both terminals. As a tell-tale sign of the centrality of this complex, artificial synapses can be formed between HEK293 cells and neurons if GluD and Nrxn are presented by the two cells, respectively, and Cblns are provided in growth media (Elegheert et al, 2016; Matsuda and Yuzaki, 2011). In the best studied case of a trans-synaptic complex involving Nrxn, a constitutively dimeric post-synaptic protein, Neuroligin, is known to bind either α- or β-Neurexin lacking the SS4 in a 2:2 stoichiometric complex (Araç et al, 2007; Chen et al, 2008; Comoletti et al, 2006; Fabrichny et al, 2007; Ichtchenko et al, 1995), and with comparable results in artificial synapse formation assays.…”

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…How the neurexin-Cbln1-GluD2 complex signals, however, remains enigmatic. Although partial crystal structures of the complex are available, they provide few clues to its mechanism of action (Elegheert et al, 2016; Cheng et al, 2016). …”

Transcellular Nanoalignment of Synaptic Function

“…Receptors are also directly involved in trans-synaptic interactions. In cerebellum, the unique postsynaptic receptor GluD2 interacts with presynaptic neurexin via hexamers of the C1q-family member cerebellin (Elegheert et al, 2016). Presynaptic neurexin-3 also modulates the recruitment of postsynaptic AMPARs during LTP (Aoto et al, 2013).…”