Neumann Detlef, Kollewe Christian, Pich Andreas, Cao Ping, Resch Klaus, Martin Michael U
Deptartment of Pharmacology, Hannover Medical School, Hannover, Germany.
J Leukoc Biol. 2008 Sep;84(3):807-13. doi: 10.1189/jlb.0507290. Epub 2008 Jun 4.
Ligand binding in the TLR/IL-1R family results in the transient formation of an intracellular signaling complex, which contains, amongst others, the serine/threonine-specific kinase IL-1R-associated kinase 1 (IRAK-1). Concomitantly, the kinase function of IRAK-1 becomes activated, resulting in massive autophosphorylation and finally in the dissociation of the initially constituted signaling complex. The death domain (DD) of IRAK-1 mediates the interaction with other molecules of the signaling complex, e.g., the adaptor MyD88, the silencer Tollip, and the activator kinase IRAK-4. The conserved threonine at position 66 (T66), located within the DD, is a putative autophosphorylation target site. Here, we provide evidence that T66 critically impacts the secondary structure of the IRAK-1 DD. Thereby, it ensures the transient manner of interactions between IRAK-1 and the other signaling molecules. This essential role, however, is not regulated by phosphorylation of T66 itself.
Toll样受体/白细胞介素-1受体（TLR/IL-1R）家族中的配体结合导致细胞内信号复合物的瞬时形成，该复合物除其他成分外，还包含丝氨酸/苏氨酸特异性激酶白细胞介素-1受体相关激酶1（IRAK-1）。与此同时，IRAK-1的激酶功能被激活，导致大量的自身磷酸化，最终导致最初形成的信号复合物解离。IRAK-1的死亡结构域（DD）介导与信号复合物中其他分子的相互作用，例如接头分子髓样分化因子88（MyD88）、沉默子Toll相互作用蛋白（Tollip）和激活激酶IRAK-4。位于DD内第66位的保守苏氨酸（T66）是一个假定的自身磷酸化靶位点。在此，我们提供证据表明，T66对IRAK-1 DD的二级结构有至关重要的影响。因此，它确保了IRAK-1与其他信号分子之间相互作用的瞬时性。然而，这一重要作用不受T66自身磷酸化的调节。
