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

Nature Structural & Molecular Biology volume 26, pages 25–34 (2019)Cite this article

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Abstract

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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Fig. 1: Complementary approaches to elucidate molecular mechanisms of signal transduction.
Fig. 2: Insights into the interaction specificity of signaling proteins.
Fig. 3: Sequence and structural features that control kinase dynamics and allostery.
Fig. 4: Allosteric activation of Ras.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Chemistry, Columbia University, New York, NY, USA

    Neel H. Shah

  2. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA

    John Kuriyan

  3. Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA

    John Kuriyan

  4. California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA

    John Kuriyan

  5. Howard Hughes Medical Institute, University of California, Berkeley, CA, USA

    John Kuriyan

  6. Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    John Kuriyan

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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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