De novo design of tyrosine and serine kinase-driven protein switches
| Autor: | Issa Yousif, Vicki H. Wysocki, Nicholas B. Woodall, David Baker, Richard S. Johnson, Michael E. P. Murphy, Florian Busch, Jesslyn E Park, Zara Y. Weinberg, Maggie Ahlrichs, Hana El-Samad, Michael J. MacCoss, Mikayla J Feldbauer |
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| Rok vydání: | 2020 |
| Předmět: |
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Molecular Protein Conformation Protein domain Amino Acid Motifs Green Fluorescent Proteins Protein Serine-Threonine Kinases Binding Competitive Catalysis Article Cell Line Serine Structure-Activity Relationship Protein Domains Structural Biology Catalytic Domain Protein Interaction Mapping Genes Synthetic Humans Tyrosine Kinase activity Phosphorylation Phosphotyrosine Molecular Biology Kinase Chemistry Calpain Calcium-Binding Proteins Hydrogen Bonding Protein-Tyrosine Kinases Cyclic AMP-Dependent Protein Kinases Recombinant Proteins Cell biology src-Family Kinases Drug Design Signal transduction Tyrosine kinase Protein Processing Post-Translational Protein Binding Signal Transduction |
| Zdroj: | Nat Struct Mol Biol |
| ISSN: | 1545-9985 |
| Popis: | Kinases play central roles in signaling cascades, relaying information from the outside to the inside of mammalian cells. De novo designed protein switches capable of interfacing with tyrosine kinase signaling pathways would open new avenues for controlling cellular behavior, but, so far, no such systems have been described. Here we describe the de novo design of two classes of protein switch that link phosphorylation by tyrosine and serine kinases to protein-protein association. In the first class, protein-protein association is required for phosphorylation by the kinase, while in the second class, kinase activity drives protein-protein association. We design systems that couple protein binding to kinase activity on the immunoreceptor tyrosine-based activation motif central to T-cell signaling, and kinase activity to reconstitution of green fluorescent protein fluorescence from fragments and the inhibition of the protease calpain. The designed switches are reversible and function in vitro and in cells with up to 40-fold activation of switching by phosphorylation. |
| Databáze: | OpenAIRE |
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