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

Pamela A. Lochhead, Gary Sibbet, Nick Morrice, Vaughn Cleghon

Research output: Contribution to journalArticle

193 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)925-936
Number of pages12
JournalCell
Volume121
Issue number6
DOIs
Publication statusPublished - 2005

Keywords

  • Autophosphorylation
  • Protein kinase

Fingerprint Dive into the research topics of 'Activation-loop autophosphorylation is mediated by a novel transitional intermediate form of DYRKs'. Together they form a unique fingerprint.

  • Cite this