Molecular Mechanisms of DYRK and GSK-3 Autophosphorylation

DYRK autophosphorylation

During maturation of the DYRK molecule, prior to release from the ribosome, the nascent kinase forms a transitional intermediate. The intermediate functions exclusively as an intramolecular tyrosine kinase and phosphorylates one substrate only, an essential tyrosine residue in the molecule’s own activation loop. The fully translated, activation loop-phosphorylated DYRK then assumes its mature conformation. The intramolecular tyrosine kinase activity is lost, and the kinase functions exclusively as an intermolecular serine / threonine kinase. The different residue and substrate specificities and sensitivities to small molecule inhibitors of the intermediate and mature kinase are outlined.

GSK-3 autophosphorylation

GSK-3 is translated and released from the ribosome. Shortly thereafter, the protein forms a transitional intermediate that exhibits canonical tyrosine kinase activity toward the molecule’s own activation loop Tyr216. Phosphorylation of Tyr216 is intramolecular and requires the chaperone activity of Hsp90. After protein maturation and Tyr216 phosphorylation, mature GSK-3 then functions as a serine / threonine kinase that phosphorylates substrates via an intermolecular mechanism. The residue phosphorylated, its sequence context, and sensitivities to inhibitors of the intermediate and mature kinase are shown.