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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
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Structural characterization of a proline-driven conformational switch within the Itk SH2 domain

Robert J Mallis1, Kristine N Brazin, D Bruce Fulton

  • 1Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA.

Nature Structural Biology
|October 29, 2002
PubMed

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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