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 journalArticlepeer-review

    198 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

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