Protein–protein interactions generate hidden feedback and feed-forward loops to trigger bistable switches, oscillations and biphasic dose–responses

Abstract

Protein–protein interactions (PPIs) defined as reversible association of two proteins to form a complex, are undoubtedly among the most common interaction motifs featured in cells. Recent large-scale proteomic studies have revealed an enormously complex interactome of the cell, consisting of tens of thousands of PPIs with numerous signalling hubs. PPIs have functional roles in regulating a wide range of cellular processes including signal transduction and post-translational modifications, and de-regulation of PPIs is implicated in many diseases including cancers and neuro-degenerative disorders. Despite the ubiquitous appearance and physiological significance of PPIs, our understanding of the dynamic and functional consequences of these simple motifs remains incomplete, particularly when PPIs occur within large biochemical networks. We employ quantitative, dynamic modelling to computationally analyse salient dynamic features of the PPI motifs and PPI-containing signalling networks varying in topological architecture. Our analyses surprisingly reveal that simple reversible PPI motifs, when being embedded into signalling cascades, could give rise to extremely rich and complex regulatory dynamics in the absence of explicit positive and negative feedback loops. Our work represents a systematic investigation of the dynamic properties of PPIs in signalling networks, and the results shed light on how this simple event may potentiate diverse and intricate behaviours in vivo.