Nature Structural Biology9, 900 - 905 (2002)
Published online: 28 October 2002; | doi:10.1038/nsb864
Structural characterization of a proline-driven conformational switch within the Itk SH2 domain
Robert J. Mallis, Kristine N. Brazin, D. Bruce Fulton
& Amy H. Andreotti
Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA.
Correspondence should be addressed to Amy H. Andreotti amyand@iastate.edu
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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