Lin Chun-Chi, Huoh Yu-San, Schmitz Karl R, Jensen Liselotte E, Ferguson Kathryn M
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Structure. 2008 Dec 10;16(12):1806-16. doi: 10.1016/j.str.2008.09.011.
Pellino proteins are RING E3 ubiquitin ligases involved in signaling events downstream of the Toll and interleukin-1 (IL-1) receptors, key initiators of innate immune and inflammatory responses. Pellino proteins associate with and ubiquitinate proteins in these pathways, including the interleukin-1 receptor associated kinase-1 (IRAK1). We determined the X-ray crystal structure of a Pellino2 fragment lacking only the RING domain. This structure reveals that the IRAK1-binding region of Pellino proteins consists largely of a previously unidentified forkhead-associated (FHA) domain. FHA domains are well-characterized phosphothreonine-binding modules, and this cryptic example in Pellino2 can drive interaction of this protein with phosphorylated IRAK1. The Pellino FHA domain is decorated with an unusual appendage or "wing" composed of two long inserts that lie within the FHA homology region. Delineating how this E3 ligase associates with substrates, and how these interactions are regulated by phosphorylation, is crucial for a complete understanding of Toll/IL-1 receptor signaling.
佩利诺蛋白是RING E3泛素连接酶，参与Toll样受体和白细胞介素-1（IL-1）受体下游的信号传导事件，而这两种受体是先天免疫和炎症反应的关键启动因子。佩利诺蛋白在这些信号通路中与蛋白质结合并使其泛素化，其中包括白细胞介素-1受体相关激酶-1（IRAK1）。我们确定了仅缺少RING结构域的佩利诺2片段的X射线晶体结构。该结构表明，佩利诺蛋白的IRAK1结合区域主要由一个以前未被识别的叉头相关（FHA）结构域组成。FHA结构域是特征明确的磷酸苏氨酸结合模块，佩利诺2中这个隐藏的结构域能够驱动该蛋白与磷酸化的IRAK1相互作用。佩利诺FHA结构域带有一个不寻常的附属物或“侧翼”，它由位于FHA同源区域内的两个长插入片段组成。阐明这种E3连接酶如何与底物结合，以及这些相互作用如何通过磷酸化进行调节，对于全面理解Toll/IL-1受体信号传导至关重要。
