The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour

Abstract

Neuronal synapses play fundamental roles in information processing, behaviour and disease. Neurotransmitter receptor complexes, such as the mammalian N-methyl-D-aspartate receptor complex (NRC/MASC) comprising 186 proteins, are major components of the synapse proteome. Here we investigate the organisation and function of NRC/MASC using a systems biology approach. Systematic annotation showed that the complex contained proteins implicated in a wide range of cognitive processes, synaptic plasticity and psychiatric diseases. Protein domains were evolutionarily conserved from yeast, but enriched with signalling domains associated with the emergence of multicellularity. Mapping of protein-protein interactions to create a network representation of the complex revealed that simple principles underlie the functional organisation of both proteins and their clusters, with modularity reflecting functional specialisation. The known functional roles of NRC/MASC proteins suggest the complex co-ordinates signalling to diverse effector pathways underlying neuronal plasticity. Importantly, using quantitative data from synaptic plasticity experiments, our model correctly predicts robustness to mutations and drug interference. These studies of synapse proteome organisation suggest that molecular networks with simple design principles underpin synaptic signalling properties with important roles in physiology, behaviour and disease.

Consolidation and translation regulation: Figure 1.

“…How do we merge this understanding with current systems biology models of molecular cognition? A number of recent studies have modeled the synaptic proteome focusing on its composition and function, typically representing the relationships between members in protein-protein interaction networks (PINs) where network membership is determined by proteomic profile and connectivity by the propensity for constituent proteins to physically interact in vitro (Collins et al 2006;Pocklington et al 2006;Fernandez et al 2009). These networks have been used to dissect out functional modules of the postsynaptic density, map disease associations, and assess the evolutionary conservation of function.…”

Reconstructing protein complexes: From proteomics to systems biology

“…It is also useful to consider domains that are missing from the complex. For example, in our synapse proteome analysis (Table 1) we see strong enrichment for proteins containing domains linked to kinase activity and calcium binding, both prominent features of signalling pathways in the CNS [11]. Conversely, we see a paucity of domains more commonly associated with DNA-binding proteins, ribosomal subunits and proteolysis.…”

“…Schematic diagrams of the MASC complex based on protein-protein interactions. Upper: The MASC protein interaction network with common protein names as described in [11]. The lower panels show the distribution of functional annotation.…”

“…A component does not have to be an unbiased representation of the full set of molecules to be of interest -in our investigation of synaptic protein complexes, we found a single, large component enriched for glutamate/calcium signal transduction and containing the majority of all proteins with known electrophysiological, behavioural and disease phenotypes. The component thus captured key aspects of network functionality, primarily those associated with signal reception and integration [11].…”

Checking the reliability of a linear-programming based approach towards detecting community structures in networks

“…To conclude this paper, we present yet another "real-life" example: We analyze a network containing 101 proteins studied by A. Pocklington et al [27] and compare our result with that obtained in [27] using the algorithm described in [26]. While this algorithm detected 13 communities all of which appear to be associated to a specific function, we only obtain six.…”