Characterization of a domain that transiently converts class 2 DYRKs into intramolecular tyrosine kinases

Sci Signal. 2010 Mar 2;3(111):ra16. doi: 10.1126/scisignal.2000579.

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Enzyme Activation
  • Genetic Complementation Test
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein Serine-Threonine Kinases / classification
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / chemistry*
  • Protein-Tyrosine Kinases / classification
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Deletion
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Substrate Specificity
  • Tyrosine / chemistry

Substances

  • Drosophila Proteins
  • Recombinant Proteins
  • Tyrosine
  • Dyrk kinase
  • mnb protein, Drosophila
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • DYRK2 protein, Drosophila