Tethered Signaling Proteins

Cells process signals by using large and complex networks of molecules that interact with and modify one another. Some of these interactions occur among molecules connected by long flexible tethers, often made of intrinsically disordered protein regions. In this review, we present recent research showing that tethered reactions (a) are ubiquitous in cells, (b) are exploited by cell signaling networks, (c) can be qualitatively and quantitatively understood using simple polymer physics, (d) give rise to categorically different features compared with molecular interactions driven by free diffusion, and (e) provide novel avenues for therapeutics and bioengineering. Recent studies have begun to shed light on cases in which the tethers must reach between different molecular assemblies that are not connected by protein scaffolding. We provide an in-depth case study of immune receptors, where such tethered signaling plays a vital role in signal integration and immune cell decisions.