The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin

The postsynaptic specialisation at glutamatergic synapses is composed of a network of proteins located within the membrane and the underlying postsynaptic density. The strong interconnectivity between the protein components is mediated by a limited number of interaction modes. Particularly abundant are PDZ domain-mediated interactions. An obstacle in understanding the fidelity of postsynaptic processes involving PDZ domains is the high degree of overlap with respect to their binding specificities. Focussing on transsynaptic adhesion molecules, we used the yeast two-hybrid system to obtain an overview of the binding specificities of selected C-terminal PDZ binding motifs. Neuroligin, a postsynaptic cell surface protein that spans the synaptic cleft and interacts with beta-neurexin, served as a starting point. Neuroligin binds to the PDZ domain-containing proteins PSD95, SAP102, Chapsyn110, S-SCAM, Magi1 and 3, Shank1 and 3, Pick1, GOPC, SPAR, Semcap3 and PDZ-RGS3. Next, we examined the relationship between neuroligin and synaptic cell adhesion molecules or glutamate receptor subunits with respect to PDZ-mediated interactions. We found a limited overlap in the PDZ-domain binding specificities of neuroligin with those of Sidekick2 and Ephrin-B2. In contrast, Syndecan2 and IgSF4 show no overlap with the PDZ-domain specificity of neuroligin, instead, they bind to GRIP and syntenin. The AMPA receptor subunit GluR2 interacts with Semcap3 and PDZ-RGS3, whereas the kainate receptor subunits GluR5 and GluR6 show weak interactions with PSD95. In summary, we can sketch a complex pattern of overlap in the binding specificities of synaptic cell surface proteins towards PDZ-domain proteins.

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