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

The postsynaptic density is an elaborate protein network beneath the postsynaptic membrane built up from the same major proteins but differing between synapses in exact composition and organization. Mutations perturbing generally occurring protein:protein interactions in this network can lead to specific effects, and the translation of biochemical effects to the system level can be especially challenging. In this work we use systems biology-based modeling of protein complex distributions in a set of major postsynaptic proteins including either a wild-type or a hypomorphic PDZ mutant Shank protein. Our results suggest that the effect of such mutations is heavily dependent on the overall availability of the protein components of the whole network. We simulated protein complex formation based on experimental data of various cell types with diverse protein abundances. The simulations revealed that mutations interfering with a single protein interaction can lead to protein complex changes only in specific cell types and in specific complexes. Although our system is currently far from a comprehensive description of the PSD, the results suggest a way to interpret specific mutations within a complex framework. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC="FIGDIR/small/562557v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@fdf273org.highwire.dtl.DTLVardef@3891deorg.highwire.dtl.DTLVardef@1f0c37borg.highwire.dtl.DTLVardef@1b1e629_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIEffect of mutations affecting protein:protein interactions can be modeled in context C_LIO_LIChanges in emerging protein complexes upon mutations are dependent on the availability of the individual proteins C_LIO_LIOur model provides conceptual explanation of confided phenotypic effects of a mutation C_LI