Molecular architecture of postsynaptic Interactomes

Abstract

The postsynaptic density (PSD) plays an essential role in the organization of the synaptic signaling machinery. It contains a set of core scaffolding proteins that provide the backbone to PSD protein-protein interaction networks (PINs). These core scaffolding proteins can be seen as three principal layers classified by protein family, with DLG proteins being at the top, SHANKs along the bottom, and DLGAPs connecting the two layers. Early studies utilizing yeast two hybrid enabled the identification of direct protein-protein interactions (PPIs) within the multiple layers of scaffolding proteins. More recently, mass-spectrometry has allowed the characterization of whole interactomes within the PSD. This expansion of knowledge has further solidified the centrality of core scaffolding family members within synaptic PINs and provided context for their role in neuronal development and synaptic function. Here, we discuss the scaffolding machinery of the PSD, their essential functions in the organization of synaptic PINs, along with their relationship to neuronal processes found to be impaired in complex brain disorders.

Keywords: Interactomes; Postsynaptic density, PSD; Protein interaction networks; Scaffolds; Synaptic signaling.

Figure 1 –

Protein domain architecture and organization of PSD scaffolding proteins. A) Figure shows protein domain composition of select PSD scaffolding proteins described in this review. Dlg4, Dlgap1, and Shank3 are representative family members of the top, middle, and bottom layers of scaffolding protein families in the PSD, respectively. B) Illustration shows the interactions between the scaffolding proteins of the PSD. DLGs, DLGAPs and SHANKs, form the three main layers while the additional scaffolds are concentrated within the middle layer.

Figure 2 –

Interactomes of the PSD Core scaffolding proteins and protein domain enrichment. (Left) Figure shows protein-protein interactions (PPIs) involving representative proteins of the three main layers of the postsynaptic density in adult mouse cortex. (Right) Protein domains found to be enriched in the interactomes of each corresponding core-scaffolding protein. All data is derived from [11].

Figure 3 –

Core scaffolding PSD interactomes and complex brain disorders. (A) Distribution of risk factors found to harbor nonsynonymous mutations in patients affected by autism spectrum disorder (ASD), intellectual disability (ID), developmental delay (DD), schizophrenia (SCZ), or multiple disorders within the interactomes of Dlg4, Dlgap1, and Shank3. Multiple risk factors are common interactors between the proteins representing the three main layers of the PSD. (B) Heatmap showing proteins found to interact with all three core scaffolding proteins (Dlg4, Dlgap1, and Shank3). Columns indicate if the protein has been implicated in contributing to complex brain disorders in the Online Mendelian Inheritance in Man (OMIM) database and through de novo nonsynonymous mutations in ASD, ID, DD, and SCZ. The abbreviations in the OMIM column are as follows: ASD – susceptibility to autism spectrum disorder, CNH – congenital hypomyelinating neuropathy, DD – related to developmental disorders, ID – Related to intellectual disability, E – related to epilepsy, MC – microcephaly. All data for PPIs and nonsynonymous mutations are derived from [11].