Abstract
In our work to date, we have translated specific atomic level structural information into a significant advance in our understanding of cellular function. Using nuclear magnetic resonance (NMR) spectroscopy, we have identified a novel conformational switch in the immunological protein tyrosine kinase Itk that is governed by a single proline residue. Furthermore, structural analysis has revealed that proline cis/trans isomerization within this kinase controls ligand recognition and mediates an interaction with the peptidyl prolyl isomerase, cyclophilin A. This is the first example of a proline isomerase interacting with a folded protein substrate. These structural observations provide the foundation upon which biochemical and cellular assays have been performed. Cyclophilin regulates the catalytic activity of the Itk tyrosine kinase thus defining a new mode of protein regulation to add to the growing list of cellular control mechanisms. Our work now lays the foundation for identification of additional proteins that are under the control of proline isomerization. We are currently extending our studies and making use of both experimental and bioinformatics approaches to identify such proline 'switches' within the complete proteome.