title: Structural characterization of a proline-driven conformational switch within the Itk SH2 domain.
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.
authors.affiliation: Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mallis
authors.forename: Kristine N
authors.initials: KN
authors.lastname: Brazin
authors.forename: D Bruce
authors.initials: DB
authors.lastname: Fulton
authors.forename: Amy H
authors.initials: AH
authors.lastname: Andreotti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057927:Hydrophobic and Hydrophilic Interactions; D007094:Imides / Q000737:chemistry; D007536:Isomerism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011392:Proline / Q000737:chemistry*; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D018909:src Homology Domains
chemical_list: D007094:Imides; D008024:Ligands; D011392:Proline; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase