Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif.
Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif.
复制标题
TIRAP 的膜靶向受到其磷酸肌醇结合基序的磷酸化的负向调节。
DOI：
10.1038/srep43043
复制
发表时间：
2017
影响因子：
4.6
通讯作者：
Capelluto,DanielGS
中科院分区：
文献类型：
--
作者：
Zhao,Xiaolin;Xiong,Wen;Xiao,Shuyan;Tang,Tuo-Xian;Ellena,JeffreyF;Armstrong,GeoffreyS;Finkielstein,CarlaV;Capelluto,DanielGS
病原体激活的Toll样受体（TLR），如TLR 2和TLR 4，二聚化并横向移动穿过质膜到磷脂酰肌醇（4，5）-二磷酸富集结构域。在这些位点，TLR与含有TIR结构域的衔接蛋白（TIRAP）相互作用，触发导致先天免疫应答的信号级联。TIRAP的膜募集由其磷酸肌醇（PI）结合基序（PBM）介导。我们发现，TIRAP PBM过渡从无序到螺旋构象的存在下，无论是两性离子胶束或单分散PI。TIRAP PBM通过碱性和非极性残基以高亲和力结合PI，有利于更有序的结构。TIRAP在其PBM内的Thr 28处磷酸化，这导致其泛素化和降解。我们证明磷酸化扭曲了TIRAP PBM的螺旋结构，减少了PI相互作用和细胞膜靶向。我们的研究提供了TIRAP膜插入的基础和从膜上去除TIRAP以避免持续的先天免疫应答的机制。
Pathogen-activated Toll-like receptors (TLRs), such as TLR2 and TLR4, dimerize and move laterally across the plasma membrane to phosphatidylinositol (4,5)-bisphosphate-enriched domains. At these sites, TLRs interact with the TIR domain-containing adaptor protein (TIRAP), triggering a signaling cascade that leads to innate immune responses. Membrane recruitment of TIRAP is mediated by its phosphoinositide (PI)-binding motif (PBM). We show that TIRAP PBM transitions from a disordered to a helical conformation in the presence of either zwitterionic micelles or monodispersed PIs. TIRAP PBM bound PIs through basic and nonpolar residues with high affinity, favoring a more ordered structure. TIRAP is phosphorylated at Thr28 within its PBM, which leads to its ubiquitination and degradation. We demonstrate that phosphorylation distorts the helical structure of TIRAP PBM, reducing PI interactions and cell membrane targeting. Our study provides the basis for TIRAP membrane insertion and the mechanism by which it is removed from membranes to avoid sustained innate immune responses.