Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs

Lochhead, P.A., Sibbet, G., Morrice, N. and Cleghon, V. (2005) Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs. Cell, 121(6), pp. 925-936. (doi: 10.1016/j.cell.2005.03.034)

Abstract

Autophosphorylation of a critical residue in the activation loop of several protein kinases is an essential maturation event required for full enzyme activity. However, the molecular mechanism by which this happens is unknown. We addressed this question for two dual-specificity tyrosine-phosphorylation-regulated protein kinases (DYRKs), as they autophosphorylate their activation loop on an essential tyrosine but phosphorylate their substrates on serine and threonine. Here we demonstrate that autophosphorylation of the critical activation-loop tyrosine is intramolecular and mediated by the nascent kinase passing through a transitory intermediate form. This DYRK intermediate differs in residue and substrate specificity, as well as sensitivity to small-molecule inhibitors, compared with its mature counterpart. The intermediate’s characteristics are lost upon completion of translation, making the critical tyrosine autophosphorylation a “one-off” inceptive event. This mechanism is likely to be shared with other kinases.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleghon, Dr Vaughan and Lochhead, Ms Pamela and Morrice, Dr Nicholas and Sibbet, Dr Gary
• Authors: Lochhead, P.A., Sibbet, G., Morrice, N., and Cleghon, V.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Cell