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

Abstract

Human tau-protein kinase I (TPK I; also known as glycogen synthase kinase 3 beta; GSK3 beta) is a serine/threonine protein kinase that participates in Alzheimer's disease. Here, binary complex structures of full-length TPK I/GSK3 beta with the ATP analogues ADP and AMPPNP solved by the X-ray diffraction method at 2.1 and 1.8 A resolution, respectively, are reported. TPK I/GSK3 beta is composed of three domains: an N-terminal domain consisting of a closed beta-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/GSK3 beta. No residues are phosphorylated, while the orientation of the activation loop in TPK I/GSK3 beta is similar to that in phosphorylated CDK2 and ERK2, suggesting that TPK I/GSK3 beta falls into a conformation that enables it to be constitutively active.

• Authors: Masaaki Aoki, Takehiro Yokota, Ikuko Sugiura, Chizuko Sasaki, Tsukasa Hasegawa, Chieko Okumura, Koichi Ishiguro, Toshiyuki Kohno, Shigetoshi Sugio, Takao Matsuzaki
• Journal: Acta crystallographica. Section D, Biological crystallography (Acta Crystallogr D Biol Crystallogr) Vol. 60 Issue Pt 3 Pg. 439-46 (Mar 2004) ISSN: 0907-4449 [Print] United States
• PMID: 14993667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenylyl Imidodiphosphate
• Adenosine Diphosphate
• Adenosine Triphosphate
• Glycogen Synthase Kinase 3 beta
• Protein Serine-Threonine Kinases
• Glycogen Synthase Kinase 3
• tau-protein kinase
• Magnesium

Topics

• Adenosine Diphosphate (analogs & derivatives, chemistry, metabolism)
• Adenosine Triphosphate (chemistry, metabolism)
• Adenylyl Imidodiphosphate (chemistry, metabolism)
• Crystallography, X-Ray
• Glycogen Synthase Kinase 3 (chemistry, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Magnesium (chemistry, metabolism)
• Protein Binding (physiology)
• Protein Serine-Threonine Kinases (chemistry, metabolism)
• Protein Structure, Tertiary
• Structural Homology, Protein