Abstract
Most biological processes are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. Although sufficient to ensure binding, these linear motifs alone are usually too short to achieve the high specificity observed, and additional contacts are often encoded in the residues surrounding the motif (i.e. the context). Here, we systematically identified all instances of peptide-mediated protein interactions of known three-dimensional structure and used them to investigate the individual contribution of motif and context to the global binding energy. We found that, on average, the context is responsible for roughly 20% of the binding and plays a crucial role in determining interaction specificity, by either improving the affinity with the native partner or impeding non-native interactions. We also studied and quantified the topological and energetic variability of interaction interfaces, finding a much higher heterogeneity in the context residues than in the consensus binding motifs. Our analysis partially reveals the molecular mechanisms responsible for the dynamic nature of peptide-mediated interactions, and suggests a global evolutionary mechanism to maximise the binding specificity. Finally, we investigated the viability of non-native interactions and highlight cases of potential cross-reaction that might compensate for individual protein failure and establish backup circuits to increase the robustness of cell networks.
Highlights
Proteins are key players in virtually all biological events that take place within and between cells
After manual filtering for the correct interaction topology, we identified high-resolution 3D structures of 810 Eukaryotic Linear Motif Database (ELM) motifs interacting with their binding domains in 611 protein pairs, which represent 47 motifs and 30 globular domains annotated in the ELM database (Figure 2)
During visual inspection of all potential domain-peptide interactions we identified 7 distinct motifs in interactions of known structure that did not match any of the patterns collected in ELM so far, binding to the domains 14-3-3, MATH, PDZ (3 new motifs) and SH2 (2 new motifs)
Summary
Proteins are key players in virtually all biological events that take place within and between cells. High-throughput interaction discovery experiments indicate only that two proteins interact, but do not provide information about the molecular details or the mechanism of the interaction. This atomic level of detail can come only from high resolution three-dimensional (3D) structures, where the residue-contacts are resolved and the protein interaction interfaces characterised [3]. In domainpeptide interactions a globular domain in one protein recognises a short linear motif from another protein, creating a relatively small interface Such interactions are found predominantly in signalling and regulatory networks [6] and, due to their transient nature, are much more difficult to handle biochemically
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