Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3β

Human tau-protein kinase I (TPK I; also known as glycogen synthase kinase 3β; GSK3β) is a serine/threonine protein kinase that participates in Alzheimer's disease. Here, binary complex structures of full-length TPK I/GSK3β with the ATP analogues ADP and AMPPNP solved by the X-ray diffraction method at 2.1 and 1.8 Å resolution, respectively, are reported. TPK I/GSK3β is composed of three domains: an N-terminal domain consisting of a closed β-barrel structure, a C-terminal domain containing a `kinase fold' structure and a small extra-domain subsequent to the C-terminal domain. The catalytic site is between the two major domains and has an ATP-analogue molecule in its ATP-binding site. The adenine ring is buried in the hydrophobic pocket and interacts specifically with the main-chain atoms of the hinge loop. The overall structure and substrate-binding residues are similar to those observed in other Ser/Thr protein kinases, while Arg141 (which is not conserved among other Ser/Thr protein kinases) is one of the key residues for specific ATP/ADP recognition by TPK I/GSK3β. No residues are phosphorylated, while the orientation of the activation loop in TPK I/GSK3β is similar to that in phosphorylated CDK2 and ERK2, suggesting that TPK I/GSK3β falls into a conformation that enables it to be constitutively active.