| STUDY |
Single Proline Isomerization Switches On Signaling Andreotti PHOTO BY AMANDA YARNELL While other symposium speakers were describing their attempts to untangle signaling webs that rely on protein-protein interactions, proteolytic activity, and phosphorylations for information transfer, author described a brand-new mode of signaling: a proline isomerization "switch." She spoke to those at the American Chemical Society national meeting in Boston last month who gathered to discuss how small molecules can probe and control various modes of signaling. Author used nuclear magnetic resonance spectroscopy to find a single proline imide bond whose conformation controls a protein's ability to recognize a substrate and activate signaling In proteins, proline imide bonds can take either the cis or trans conformation. But because the activation energy required to switch between conformations is high (about 20 kcal per mole), the vast majority of proline bonds in folded proteins pick one--usually trans--and stick with it. Authors have found a protein in which a single proline imide bond exists sometimes in the cis conformation and sometimes in the trans. A few other examples of proline switches do exist. "But this proline switch is the first one to control ligand recognition." The protein, known as Itk, is a signaling enzyme that helps to jump-start the body's immune response by catalyzing the phosphorylation of a key tyrosine residue in another protein. The proline that changes conformation is located in Itk's substrate-binding domain. When the proline is in the trans conformation, Itk can interact with the substrate and turn on signaling. When the same proline is cis, however, Itk dimerizes--although the functional consequences of dimerization are still unclear, Andreotti says. Binding of cyclosporin A, an enzyme that catalyzes the isomerization of proline peptidyl bonds, represses Itk activity, presumably by stabilizing the transition state between the two conformers. By studying Itk's proline switch in detail, "we hope to figure out how to identify other proteins that use proline isomerization to control signaling." |
| UPDATE | 09.02 |
| AUTHOR | This data is not available for free |
| LITERATURE REF. | This data is not available for free |
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