Structural Basis for the Interaction of TAK1 Kinase with its Activating Protein TAB1

Transforming growth factor-β (TGF-β)-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 β, interleukin-1 and tumour necrosis factor-α. 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 α-helix in the TAK1 binding domain of TAB1, providing the basis for an intimate hydrophobic association between the protein activator and its target.