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.
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We thank P. Bandaru and R. Ranganathan for insights and stimulating discussions. N.H.S. is a funded by a Damon Runyon–Dale F. Frey Award for Breakthrough Scientists from the Damon Runyon Cancer Research Foundation. J.K. is funded by NIH grant P01 A1091580.
The authors declare no competing interests.
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Shah, N.H., Kuriyan, J. Understanding molecular mechanisms in cell signaling through natural and artificial sequence variation. Nat Struct Mol Biol 26, 25–34 (2019). https://doi.org/10.1038/s41594-018-0175-9
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