Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90
Two distinct regions of the immunophilin-like protein XAP2 regulate dioxin receptor function and interaction with hsp90
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DOI：
10.1074/jbc.m200053200
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发表时间：
2002-04-05
影响因子：
4.8
通讯作者：
Pongratz, I
中科院分区：
文献类型：
--
作者：
Kazlauskas, A;Poellinger, L;Pongratz, I
二恶英(芳香烃)受体是一种配体诱导的转录因子，它介导细胞对各种外来化合物的反应，如二恶英。在缺乏配体的情况下，该受体与分子伴侣HSP90和含有免疫亲和素样蛋白XAP2的四肽重复序列(TPR-)结合。XAP2参与调节二恶英受体在细胞内的定位，保护二恶英受体不被降解。本研究构建了一系列XAP2突变体，以确定介导与二恶英受体-热休克蛋白90复合体相互作用和调节受体功能的结构基序(S)。免疫沉淀实验表明，XAP2的C末端部分，包括TPR基序和TPR基序外的区域，需要与HSP90直接接触。XAP2的N端部分是二恶英受体-HSP90-XAP2三元复合体稳定所必需的。此外，XAP2 N-末端区域的完整性对于XAP2调节二恶英受体的细胞内定位是必不可少的。综上所述，这些数据表明，XAP2的两个不同区域调节二恶英受体的功能和与hps 90的相互作用，说明了HSP90分子伴侣机制调控二恶英受体信号的复杂性。
The dioxin (aryl hydrocarbon) receptor is a ligand inducible transcription factor, which mediates cellular responses to a variety of xenobiotic compounds such as dioxins. In the absence of ligand the receptor is associated with the molecular chaperone hsp90 and the tetratricopeptide repeat (TPR-) containing immunophilin-like protein XAP2. XAP2 has been implicated in regulation of the intracellular localization of the dioxin receptor and protection of the receptor against degradation. In this study a series of XAP2 mutants has been generated in order to identify the structural motif(s) mediating interaction with the dioxin receptor-hsp90 complex and modulation of receptor function. Immunoprecipitation experiments demonstrated that the C-terminal part of XAP2, including the TPR motifs and the region outside the TPR motifs, was required to directly contact hsp90. The N-terminal part of XAP2 was required for the stability of the ternary dioxin receptor-hsp90-XAP2 complex. In addition, the integrity of the N-terminal region of XAP2 was essential for XAP2 to regulate the intracellular localization of the dioxin receptor. In conclusion, these data demonstrate that two distinct regions of XAP2 modulate dioxin receptor function and interaction with hps90, illustrating the complexity in regulation of dioxin receptor signaling by the hsp90 molecular chaperone machinery.