Occurrence of ordered and disordered structural elements in postsynaptic proteins supports optimization for interaction diversity

Abstract

The human postsynaptic density is an elaborate network comprising thousands of proteins, playing a vital role in the molecular events of learning and the formation of memory. Despite our growing knowledge of specific proteins and their interactions, atomic-level details of their full three-dimensional structure and their rearrangements are mostly elusive. Advancements in structural bioinformatics enabled us to depict the characteristic features of proteins involved in different processes aiding neurotransmission. We show that postsynaptic protein-protein interactions are mediated through the delicate balance of intrinsically disordered regions and folded domains, contributing to a high level of protein modularity. We introduce structure and regulation based descriptors to assess the diversity of interactions required to maintain the synaptic plasticity. Our approach reveals that the postsynaptic proteome has markedly different features compared to those of other proteins included in the human proteome. Graphical abstractKey terms

Distribution of disease-causing germline mutations in coiled-coils suggests essential role of their N-terminal region

“…The role of postsynaptic density (PSD) proteins in neural degeneration is often revisited in various papers 44,45 . In our recent article, we showed that postsynaptic density proteins are exceptionally modular, and they are highly enriched in coiledcoil regions 46 . These results further underline the critical role of coiled-coil containing proteins in the PSD, and advocates the importance of modular protein structures in disease development.…”

PSINDB: A comprehensive database of postsynaptic protein-protein interactions

“…PSD proteins exhibit a high degree of multivalency presenting multiple binding sites stacked into single proteins. This multivalency aids the formation of an elaborate and dynamic network via highly modular architecture, provided by distinct structural and functional elements [7]. Intrinsically disordered regions (IDRs) were shown to be critical components for network assembly in the PSD [8], often by containing short linear motifs mediating transient interactions [9], post-translational modification sites regulating interactions as switches [10] and more.…”