Crystal structure of the TAO2 kinase domain: activation and specificity of a Ste20p MAP3K.
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.
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Tianjun
T
Zhou
Malavika
M
Raman
Yan
Y
Gao
Svetlana
S
Earnest
Zhu
Z
Chen
Mischa
M
Machius
Melanie H
MH
Cobb
Elizabeth J
EJ
Goldsmith
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D003461:Crystallography; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D040681:Structural Homology, Protein; D013379:Substrate Specificity
D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C122016:Taok2 protein, rat; D020930:MAP Kinase Kinase Kinases; D048669:MAP Kinase Kinase 6