Abstract
The postsynaptic density (PSD) is a dense protein network playing a key role in information processing during learning and memory, and is also indicated in a number of neurological disorders. Efforts to characterize its detailed molecular organization are encumbered by the large variability of the abundance of its constituent proteins both spatially, in different brain areas, and temporally, during development, circadian rhythm, and also in response to various stimuli. In this study we ran large-scale stochastic simulations of protein binding events to predict the presence and distribution of PSD complexes. We simulated the interactions of seven major PSD proteins (NMDAR, AMPAR, PSD-95, SynGAP, GKAP, Shank3, Homer1) based on previously published, experimentally determined protein abundance data from 22 different brain areas and 42 patients (altogether 524 different simulations). Our results demonstrate that the relative ratio of the emerging protein complexes can be sensitive to even subtle changes in protein abundances and thus explicit simulations are invaluable to understand the relationships between protein availability and complex formation. Our observations are compatible with a scenario where larger supercomplexes are formed from available smaller binary and ternary associations of PSD proteins. Specifically, Homer1 and Shank3 self-association reactions substantially promote the emergence of very large protein complexes. The described simulations represent a first approximation to assess PSD complex abundance, and as such, use significant simplifications. Therefore, their direct biological relevance might be limited but we believe that the major qualitative findings can contribute to the understanding of the molecular features of the postsynapse.
Highlights
Complexity of the human brain is often attributed to the diversity of the neuronal network
We found that the relationship between single protein and protein complex abundances can be non-trivial, since similar complex distributions can emerge from distinct relative protein abundances and quite different protein complexes can be formed from almost similar initial protein abundances
The postsynaptic density (PSD) is an intricate network of proteins located at the postsynaptic membrane and is responsible for signal processing
Summary
Complexity of the human brain is often attributed to the diversity of the neuronal network. There is growing experimental evidence showing that individual synapses are highly diverse in terms of the relative abundance of their constituent proteins [1]. These observations have led to the formulation of the synaptomic theory [2] that emphasises the genetic background and experience-dependent changes in the molecular composition of synapses. The postsynaptic density (PSD) is an intricate network of proteins located at the postsynaptic membrane and is responsible for signal processing. Understanding the organization of the protein network is key to describe physiological and pathological molecular processes underlying learning, memory and behavior
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