Understanding molecular mechanisms in cell signaling through natural and artificial sequence variation

The functionally tolerated sequence space of proteins can now be explored in an unprecedented way, owing to the expansion of genomic databases and the development of high-throughput methods to interrogate protein function. For signaling proteins, several recent studies have shown how the analysis of sequence variation leverages the available protein-structure information to provide new insights into specificity and allosteric regulation. In this Review, we discuss recent work that illustrates how this emerging approach is providing a deeper understanding of signaling proteins. Shah and Kuriyan highlight how the analysis of sequence variation synergizes with protein structure information, to provide new insights into specificity and allosteric regulation of signaling proteins.