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

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 23 different brain areas and 43 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.

Simulated complexes formed from a set of postsynaptic proteins suggest a localised effect of a hypomorphic Shank mutation

“…Cytocast and its precursor have been shown to be able to effectively model protein complex distributions even in whole cells [20]. Similarly to our previous study [15], we have investigated a simplified PSD model using only 7 major PSD proteins: AMPAR, NMDAR, PSD-95, Homer1, GKAP, SynGAP, and Shank1. We have replaced Shank3 with Shank1 relative to our previous study because the mutation that was introduced has been described in Shank1 (see below).…”

“…Overall, we have simulated protein complexes in 524 different data sets originating from 27 brain region types, as in our previous work [15]. The source data sets contain mRNA expression levels [18] that we have translated into protein abundance [15].…”

“…Overall, we have simulated protein complexes in 524 different data sets originating from 27 brain region types, as in our previous work [15]. The source data sets contain mRNA expression levels [18] that we have translated into protein abundance [15]. It should be noted that no information about the individuals from which the data are derived is available, whether they can be considered as in a healthy or diseased condition.…”

“…Besides state-of-the-art microscopic techniques [13, 14], simulation approaches might contribute to our more detailed understanding of the supramolecular structure of the PSD and its changes upon stimuli and mutations. We have previously described extensive simulations on protein complexes using a simplified model of the PSD containing 7 major proteins and have shown that the correspondence between protein component abundance and the distribution of the complexes formed is nontrivial [15]. Specifically, the classification of PSDs based on the abundance of constituent proteins can largely differ from the classification based on complex distributions, a feature supposedly more closely linked to the biological function of the network.…”

“…As a model hypomorphic mutation, we have chosen one that can be estimated to cause the decrease of a specific binding interaction between 2-and 10-fold. We use the same model system as in our previous work, composed of seven major PSD proteins, except for replacing Shank3 with Shank1 (NMDAR, AMPAR, PSD-95, SynGAP, GKAP, Homer1, Shank1) [15], and more than 500 brain regions with different protein levels [18].…”