Tsinghua-Peking Center for Life Sciences and MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Sci China Life Sci. 2013 Jul;56(7):653-60. doi: 10.1007/s11427-013-4494-0. Epub 2013 May 31.
The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-β activated kinase 1 (TAK1) is an upstream kinase in p38α signaling, and its full activation requires a specific activator, the TAK1-binding protein (TAB1). TAB1 was also shown to be an inducer of p38α's autophosphorylation and/or a substrate driving the feedback control of p38α signaling. Here we determined the complex structure of the unphosphorylated p38α 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 p38α. Our structural and biochemical analyses suggest that TAB1 is a reasonable substrate of p38α, yet the interaction between the docking peptide and p38α may not be sufficient to trigger trans-autophosphorylation of p38α.
丝裂原活化蛋白激酶（MAPK）p38α 是许多细胞过程中的关键调节剂，其活性受到上游激酶、磷酸酶和其他调节剂的严格调节。转化生长因子-β激活激酶 1（TAK1）是 p38α 信号通路中的上游激酶，其完全激活需要一种特定的激活剂，即 TAK1 结合蛋白（TAB1）。TAB1 也被证明是 p38α 自身磷酸化的诱导剂和/或驱动 p38α 信号反馈控制的底物。在这里，我们确定了未磷酸化的 p38α 和 TAB1 对接肽的复合物结构，该结构表明 TAB1 肽结合到经典的 MAPK 对接槽，并诱导 p38α 的长程构象变化。我们的结构和生化分析表明，TAB1 是 p38α 的合理底物，但对接肽与 p38α 之间的相互作用可能不足以触发 p38α 的转位自身磷酸化。
