Peptides mediating interaction networks: new leads at last

A growing number of protein interactions are found to be mediated by a large globular region in one protein binding to a comparatively short, peptide stretch in another. Regions that bind a common protein often show a similar sequence pattern or linear motif that mediates the binding. The past year has seen reports of new techniques that can uncover these motifs directly from interaction data. These studies have suggested that the fraction of interactions mediated by these regions is greater than previously anticipated. Concurrently, other work has demonstrated that it is possible to target these interactions using small molecules. Together these developments hold great promise for future efforts to target chemically precise details of complex systems.

Introduction

Protein–protein interaction networks are having a growing impact on molecular biology. By suggesting details of potential binding partners they provide a cellular context that can be very illuminating about function. These networks also provide a framework for both studying biological systems and suggesting points of intervention to perturb them. However, the picture is currently limited, because techniques for determining interactions at the genome-scale (e.g. [1•, 2•, 3, 4]) lack details as to how they are mediated. Many interactions where details are known (e.g. from three-dimensional structures or predicted by various modelling techniques [5, 6]), show them to occur over large surfaces and this indeed seems to be the prevailing view of how most interactions occur. Interactions between large surfaces are normally difficult to perturb chemically, which has made them rather out of favour among those attempting to design inhibitors to target particular biological processes [7] (although some startling successes are challenging this view, e.g. [8, 9••]).

A growing number of interactions are now known to be mediated by short linear peptides: that is, where a smaller surface on one globular protein (or domain) binds to a short peptide segment in another. These globular proteins (or domains) often bind to different regions in multiple partners, and analysis often reveals an underlying consensus pattern or linear motif that captures the key features of the regions. Exciting recent work has shown that interactions mediated by these peptides are more amenable to chemical targeting than the larger interaction surfaces. This review discusses recent advances in the discovery of peptide/linear motif mediated interactions, and highlights some exciting new developments in their targeting by small molecules.