Abstract
Transforming growth factor-beta (TGF-beta)-activated kinase 1 (TAK1) is a member of the MAPKKK family of protein kinases, and is involved in intracellular signalling pathways stimulated by transforming growth factor beta, interleukin-1 and tumour necrosis factor-alpha. TAK1 is known to rely upon an additional protein, TAK1-binding protein 1 (TAB1), for complete activation. However, the molecular basis for this activation has yet to be elucidated. We have solved the crystal structure of a novel TAK1 chimeric protein and these data give insight into how TAK1 is activated by TAB1. Our results reveal a novel binding pocket on the TAK1 kinase domain whose shape complements that of a unique alpha-helix in the TAK1 binding domain of TAB1, providing the basis for an intimate hydrophobic association between the protein activator and its target.
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry*
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / isolation & purification
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Adaptor Proteins, Signal Transducing / metabolism*
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Adenosine / metabolism
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Amino Acid Sequence
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Baculoviridae / genetics
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Binding Sites
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Crystallography, X-Ray
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Enzyme Activation
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Humans
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Hydrophobic and Hydrophilic Interactions
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Kinetics
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MAP Kinase Kinase Kinases / chemistry*
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MAP Kinase Kinase Kinases / metabolism*
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Mass Spectrometry
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Models, Molecular
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Molecular Sequence Data
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Protein Binding
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Sequence Homology, Amino Acid
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Substrate Specificity
Substances
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Adaptor Proteins, Signal Transducing
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Recombinant Fusion Proteins
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TAB1 protein, human
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Adenosine