TY - JOUR
T1 - Crystal structure of the TAO2 kinase domain
T2 - Activation and specificity of a Ste20p MAP3K
AU - Zhou, Tianjun
AU - Raman, Malavika
AU - Gao, Yan
AU - Earnest, Svetlana
AU - Chen, Zhu
AU - Machius, Mischa
AU - Cobb, Melanie H.
AU - Goldsmith, Elizabeth J.
N1 - Funding Information:
We thank Radha Akella and Chung-I Chang for technical support, Xiaoshan Min for providing rat MEK6 plasmid, and Eric Shaefer for anti-phosphoMEK3/6 antibodies. We thank Diana Tomchick as well as the staff at Argonne National Laboratory for help with Synchrotron data collection. This research was supported by NIH grants DK46993 and GM53032 and grants I1128 and I1143 from the Welch Foundation. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Biological and Environmental Research, under Contract No. W-31-109-ENG-38.
PY - 2004/10
Y1 - 2004/10
N2 - TAO2 is a mitogen-activated protein kinase kinase kinase (MAP3K) that doubly phosphorylates and activates the MAP kinase kinases (MAP2Ks) MEK3 and MEK6. The structure of the kinase domain of TAO2 (1-320) has been solved in its phosphorylated active conformation. The structure, together with structure-based mutagenic analysis, reveals that positively charged residues in the substrate binding groove mediate the first step in the dual phosphorylation of MEK6, on the threonine residue in the motif DS*VAKT*I (*denotes phosphorylation site) of MEK6. TAO2 is a Ste20p homolog, and the structure of active TAO2, in comparison with that of low-activity p21-activated protein kinase (PAK1), a Ste20p-related MAP4K, reveals how this group of kinases is activated by phosphorylation. Finally, active TAO2 displays unusual interactions with ATP, involving, in part, a subgroup-specific C-terminal extension of TAO2. The observed interactions may be useful in making specific inhibitors of TAO kinases.
AB - TAO2 is a mitogen-activated protein kinase kinase kinase (MAP3K) that doubly phosphorylates and activates the MAP kinase kinases (MAP2Ks) MEK3 and MEK6. The structure of the kinase domain of TAO2 (1-320) has been solved in its phosphorylated active conformation. The structure, together with structure-based mutagenic analysis, reveals that positively charged residues in the substrate binding groove mediate the first step in the dual phosphorylation of MEK6, on the threonine residue in the motif DS*VAKT*I (*denotes phosphorylation site) of MEK6. TAO2 is a Ste20p homolog, and the structure of active TAO2, in comparison with that of low-activity p21-activated protein kinase (PAK1), a Ste20p-related MAP4K, reveals how this group of kinases is activated by phosphorylation. Finally, active TAO2 displays unusual interactions with ATP, involving, in part, a subgroup-specific C-terminal extension of TAO2. The observed interactions may be useful in making specific inhibitors of TAO kinases.
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U2 - 10.1016/j.str.2004.07.021
DO - 10.1016/j.str.2004.07.021
M3 - Article
C2 - 15458637
AN - SCOPUS:4644232397
SN - 0969-2126
VL - 12
SP - 1891
EP - 1900
JO - Structure
JF - Structure
IS - 10
ER -