Emerging maps of allosteric regulation in cellular networks

Allosteric regulation is classically defined as action at a distance, where a perturbation outside of a protein active site affects function. While this definition has motivated many studies of allosteric mechanisms at the level of protein structure, translating these insights to the allosteric regulation of entire cellular processes – and their crosstalk – has received less attention, despite the broad importance of allostery for cellular regulation foreseen by Jacob and Monod. Here, we revisit an evolutionary model for the widespread emergence of allosteric regulation in colocalized proteins, describe supporting evidence, and discuss emerging advances in mapping allostery in cellular networks that link precise and often allosteric perturbations at the molecular level to functional changes at the pathway and systems levels. •Allostery enables co-regulation of cellular pathways.•Recent studies support a general model for emergence of allosteric regulation in protein networks.•Combining targeted perturbations with systems-level profiling allows for unbiased discovery of allosteric regulation.•Predictive models of allostery require data integration bridging molecular and cellular scales.