Multiple IRAK1 autophosphorylation steps

Phosphorylation of IRAK-1 is due to three sequential phosphorylation steps, which leads to full or hyper-phopshorylation of IRAK1. Under in vitro conditions these are all autophosphorylation events. First, Thr-209 is phosphorylated resulting in a conformational change of the kinase domain. Next, Thr-387 in the activation loop is phosphorylated, leading to full enzymatic activity. Several additional residues are phosphorylated in the proline-, serine-, and threonine-rich (ProST) region between the N-terminal death domain and kinase domain. Hyperphosphorylation of this region leads to dissociation of IRAK1 from the activated receptor complex. The kinase activity of IRAK1 is dispensable for IL1-induced NFkB and MAP kinase activation (Knop & Martin, 1999), unlike that of IRAK4 (Suzuki et al. 2002; Kozicak-Holbro et al. 2007), It has been suggested that IRAK1 primarily acts as an adaptor for TRAF6 (Conze et al. 2008).

IRAK-1磷酸化过程由三个连续的磷酸化步骤组成，导致IRAK1发生完全或超磷酸化。在体外条件下，这些过程均为自磷酸化事件。首先，Thr-209位点发生磷酸化，导致激酶结构域的构象变化。随后，激活环中的Thr-387位点被磷酸化，进而引发酶的完全活性。在N端死亡结构域与激酶结构域之间的富含脯氨酸、丝氨酸和苏氨酸（ProST）区域，还有多个位点被磷酸化。该区域的超磷酸化导致IRAK1从活化的受体复合物中解离。IRAK1的激酶活性对于IL1诱导的NFkB和MAP激酶的激活并非必需（Knop & Martin, 1999），与IRAK4（Suzuki et al. 2002; Kozicak-Holbro et al. 2007）的情况不同。有研究表明，IRAK1主要作为TRAF6的适配器发挥作用（Conze et al. 2008）。