Mechanism of dual specificity kinase activity of DYRK1A

• DOI: 10.1111/febs.12411
• Publication Date: 2013-06-28T07:48:53Z
• Authors: Agnes Walte; Katharina Rüben; Ruth Birner‐Gruen...; Christian Preisinger; Simone Bamberg‐Le...; Nikolaus Hilz; Franz Bracher; Walter Becker
• Keywords: Models, Molecular; Threonine; 0303 health sciences; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Transfection; Recombinant Proteins; Protein Structure, Tertiary; Rats; Substrate Specificity; Kinetics; 03 medical and health sciences; Biocatalysis; Escherichia coli; Serine; Animals; Humans; Thermodynamics; Tyrosine; Phosphorylation; Protein Processing, Post-Translational; HeLa Cells

The function of many protein kinases is controlled by the phosphorylation a critical tyrosine residue in activation loop. Dual specificity tyrosine-phosphorylation-regulated (DYRKs) autophosphorylate on this but phosphorylate substrates aliphatic amino acids. This study addresses mechanism dual kinase activity DYRK1A and related kinases. Tyrosine autophosphorylation occurred rapidly during vitro translation did not depend non-catalytic domains or other proteins. Expression bacteria as well mammalian cells revealed that restricted to co-translational Moreover, mature was still capable autophosphorylation. Point mutants DYRK2 lacking loop showed enhanced activity. A series structurally diverse inhibitors used pharmacologically distinguish different conformational states catalytic domain are hypothesized account for All tested compounds inhibited substrate with higher potency than none differentially threonine Finally, cyclin-dependent kinase-like (CLKs), which lack tyrosine, autophosphorylated both living cells. We propose model DYRK autoactivation stabilizes conformation serine/threonine without disabling phosphorylation. probably applies maturation.