Crystal structure of the p38α MAP kinase in complex with a docking peptide from TAB1

The mitogen-activated protein kinase (MAPK) p38 alpha is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-beta activated kinase 1 (TAK1) is an upstream kinase in p38 alpha signaling, and its full activation requires a specific activator, the TAK1-binding protein (TAB1). TAB1 was also shown to be an inducer of p38 alpha's autophosphorylation and/or a substrate driving the feedback control of p38 alpha signaling. Here we determined the complex structure of the unphosphorylated p38 alpha and a docking peptide of TAB1, which shows that the TAB1 peptide binds to the classical MAPK docking groove and induces long-range conformational changes on p38 alpha. Our structural and biochemical analyses suggest that TAB1 is a reasonable substrate of p38 alpha, yet the interaction between the docking peptide and p38 alpha may not be sufficient to trigger trans-autophosphorylation of p38 alpha.