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Sci. Signal., 2 March 2010
Vol. 3, Issue 111, p. ra16
[DOI: 10.1126/scisignal.2000579]

RESEARCH ARTICLES

Characterization of a Domain That Transiently Converts Class 2 DYRKs into Intramolecular Tyrosine Kinases

Ross Kinstrie1*, Nathan Luebbering2*, Diego Miranda-Saavedra3, Gary Sibbet4, Jingfen Han2, Pamela A. Lochhead5, and Vaughn Cleghon2{dagger}

1 Department of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
2 Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
3 Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
4 Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
5 Laboratory of Molecular Signalling, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.

* These authors contributed equally to this work.

Abstract: Dual-specificity tyrosine phosphorylation–regulated kinases (DYRKs) autophosphorylate an essential tyrosine residue in their activation loop and phosphorylate their substrates on serine and threonine residues. Phosphorylation of the activation loop tyrosine occurs intramolecularly, is mediated by a short-lived transitional intermediate during protein maturation, and is required for functional serine-threonine kinase activity of DYRKs. The DYRK family is separated into two subclasses. Through bioinformatics and mutational analyses, we identified a conserved domain in the noncatalytic N terminus of a class 2 DYRK that was required for autophosphorylation of the activation loop tyrosine but not for the phosphorylation of serine or threonine residues in substrates. We propose that this domain, which we term the NAPA domain, provides a chaperone-like function that transiently converts class 2 DYRKs into intramolecular kinases capable of autophosphorylating the activation loop tyrosine. The conservation of the NAPA domain from trypanosomes to humans indicates that this form of intramolecular phosphorylation of the activation loop is ancient and may represent a primordial mechanism for the activation of protein kinases.

{dagger} To whom correspondence should be addressed. E-mail: vaughn.cleghon{at}cchmc.org

Citation: R. Kinstrie, N. Luebbering, D. Miranda-Saavedra, G. Sibbet, J. Han, P. A. Lochhead, V. Cleghon, Characterization of a Domain That Transiently Converts Class 2 DYRKs into Intramolecular Tyrosine Kinases. Sci. Signal. 3, ra16 (2010).

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