Structural insight into nucleotide recognition in tau-protein kinase I/glycogen synthase kinase 3 beta.
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.
Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiohya, Machida, Tokyo 194-8511, Japan.
Masaaki
M
Aoki
Takehiro
T
Yokota
Ikuko
I
Sugiura
Chizuko
C
Sasaki
Tsukasa
T
Hasegawa
Chieko
C
Okumura
Koichi
K
Ishiguro
Toshiyuki
T
Kohno
Shigetoshi
S
Sugio
Takao
T
Matsuzaki
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000266:Adenylyl Imidodiphosphate / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D040681:Structural Homology, Protein
D000266:Adenylyl Imidodiphosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase; D008274:Magnesium