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, and this duality is also imprinted in the amino acid sequence. We introduce Diversity of Potential Interactions (DPI), a structure and regulation based descriptor to assess the diversity of interactions. Our approach reveals that the postsynaptic proteome has its own characteristic features and these properties reliably discriminate them from other proteins of the human proteome. Our results suggest that postsynaptic proteins are especially susceptible to forming diverse interactions with each other, which might be key in the reorganization of the postsynaptic density (PSD) in molecular processes related to learning and memory.

Integrative structural dynamics probing of the conformational heterogeneity in synaptosomal-associated protein 25

“… 1 – 3 The intrinsic disorder with high conformational plasticity is essential for forming transient yet stable signaling protein complexes 4 and key transcription regulators. 5 In synapses, IDPs and proteins containing intrinsically disordered regions (IDRs) are important in neurotransmitter release, 6 the formation of junctions, 7 remodeling of the postsynaptic density, 8 and signaling in the cytoplasmic region of several membrane receptors. 9 , 10 The high degree of conformational heterogeneity of IDPs is due to the lack of a well-defined secondary and tertiary structure organization, the biased amino acid composition, and low sequence complexity.…”

PSINDB: the postsynaptic protein–protein interaction database

“…Each entry in PSINDB also contains structural information about the protein ( Figure 1C ). Nearly all postsynaptic proteins exhibit high modularity ( 9 ), where the ordered and disordered modules mediate different interactions. Coiled-coils are also essential players in the PS: they often provide spacer and linker functions, aiding the formation of supramolecular assemblies by connecting distant compartments and proteins.…”

“…Protein–protein interactions (PPIs) play an essential role both in the maintenance of synaptic plasticity and in disease emergence. Postsynaptic proteins exhibit a high degree of multivalency presenting multiple binding sites, and this multivalency aids the formation of an elaborate and dynamic network provided by distinct structural and functional elements ( 9 ). Intrinsically disordered regions were shown to be critical components for network assembly in the PS ( 10 ), often by containing short linear motifs mediating transient interactions ( 11 ) and post-translational modification sites regulating interactions as switches ( 12 ), among others.…”

Diversity of synaptic protein complexes as a function of the abundance of their constituent proteins: A modeling approach

“…To get a deeper understanding into the actual mechanism of the PSD, we need to move toward explicit modeling of the protein complexes formed. Our recent sequence analysis [4] suggests that PSD proteins are particularly enriched in domains and regions mediating protein-protein interactions, resulting in a high diversity of possible interactions. Thus, many different complexes and networks can be built from the very same elements depending on their abundance and availability.…”