Editors' ChoiceStructural Biology

Proline Isomerization Regulates ITK

STKE  26 Feb 2002:
Vol. 2002, Issue 121, pp. tw83
DOI: 10.1126/stke.2002.121.tw83

Interleukin-2 tyrosine kinase (ITK) is a T cell-specific member of the Tec family of nonreceptor tyrosine kinases. Brazin et al. determined by nuclear magnetic resonance (NMR) studies that the ITK SH2 domain existed in two conformations reflecting the protein with Pro287 bond in the cis or trans configuration. The SH2 domain of ITK can bind in a phosphotyrosine-dependent manner (substrate binding) or can interact in a phosphotyrosine-independent manner with the SH3 domain of another ITK molecule. Chemical shift perturbations in the presence of the ligands showed that the cis conformation was required for the phosphotyrosine-independent binding to ITK SH3 domains, and the trans conformation was required for phosphopeptide binding. The ITK SH2 domain interacted specifically with the peptidyl-prolyl cis/trans isomerase cyclophilin A (CypA), as measured by NMR. In vitro and in vivo CypA interacted with and inhibited ITK kinase activity. The authors propose that CypA is an endogenous regulator of ITK activity, and the ITK ligand recognition is governed by the conformation of the Asn286-Pro287bond.

K. N. Brazin, R. J. Mallis, D. B. Fulton, A. H. Andreotti, Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A. Proc. Natl. Acad. Sci. U.S.A. 99, 1899-1904 (2002). [Abstract] [Full Text]