Characterization of a domain that transiently converts class 2 DYRKs into intramolecular tyrosine kinases.
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.
Kinstrie
Ross
R
1Department of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.
Luebbering
Nathan
N
Miranda-Saavedra
Diego
D
Sibbet
Gary
G
Han
Jingfen
J
Lochhead
Pamela A
PA
Cleghon
Vaughn
V
D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005816:Genetic Complementation Test; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013379:Substrate Specificity; D014443:Tyrosine / Q000737:chemistry; D000097603:Dyrk Kinases
D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D014443:Tyrosine; D000097603:Dyrk Kinases; C092066:mnb protein, Drosophila; C502549:DYRK2 protein, Drosophila