Abstract
Interleukin-2 tyrosine kinase (Itk) is a T cell-specific kinase required for a proper immune response following T cell receptor engagement. In addition to the kinase domain, Itk is composed of several noncatalytic regulatory domains, including a Src homology 2 (SH2) domain that contains a conformationally heterogeneous Pro residue. Cis-trans isomerization of a single prolyl imide bond within the SH2 domain mediates conformer-specific ligand recognition that may have functional implications in T cell signaling. To better understand the mechanism by which a proline switch regulates ligand binding, we have used NMR spectroscopy to determine two structures of Itk SH2 corresponding to the cis and trans imide bond-containing conformers. The structures indicate that the heterogeneous Pro residue acts as a hinge that modulates ligand recognition by controlling the relative orientation of protein-binding surfaces.
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Acknowledgements
The authors thank M. Hargrove and E. Pletneva for critical review of the manuscript. We also thank J. Thomas for his generosity in the use of his laboratory and equipment for carrying out the isoelectric focusing gels. Support for this work was provided by a National Institutes of Health grant and a grant from the Roy J. Carver Charitable Trust.
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Mallis, R., Brazin, K., Fulton, D. et al. Structural characterization of a proline-driven conformational switch within the Itk SH2 domain. Nat Struct Mol Biol 9, 900–905 (2002). https://doi.org/10.1038/nsb864
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DOI: https://doi.org/10.1038/nsb864
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