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基于KEAP1 BTB域的传感器活动的双向调节

Takafumi Suzuki¹, Kenji Takagi², Tatsuro Iso³

¹Department of Biochemistry & Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.

|October 15, 2025

概括

电友化学物质修改KEAP1 BTB域,改变其结构以调节NRF2-KEAP1-CUL3通路. 这种机制通过调节蛋白质稳定性来控制细胞应激反应.

科学领域:

生物化学生物化学
分子生物学分子生物学
细胞生物学细胞生物学

背景情况:

KEAP1-CUL3 基因酶复合体对于调节NRF2转录因子的稳定性至关重要,在细胞应激反应中发挥关键作用.
KEAP1的BTB域作为电友化合物的传感器,但电友识别和抑制BTB活动的确切机制尚未完全理解.

研究的目的:

阐明电友修饰调节KEAP1 BTB域活动的分子机制.
研究电友如何改变BTB同位体的空间布局,并影响KEAP1-CUL3酶活性.

主要方法:

对KEAP1 BTB域的共晶结构分析.
使用NRF2诱导的CDDO衍生物和合成电友化合物的功能研究.
调查Cys151在电友感应和KEAP1-CUL3复杂亲和力调节中的作用.

主要成果:

电友性修饰诱导KEAP1 BTB同位体的空间布局发生变化,影响其结合酶活性.
通过NRF2诱导剂对Cys151的修改会改变CUL3结合部位,从而降低KEAP1-CUL3复合物的亲和力.
一个向Cys151的NRF2抑制剂会导致BTB同位体的相反重新排列.

结论:

这项研究揭示了KEAP1 BTB域感知电友并调节KEAP1-CUL3无处不在酶活性的精确分子机制.
了解这种机制可以了解细胞应激反应途径和涉及NRF2调节的潜在治疗策略.

关键词:

BTB 域名 BTB 域名这就是 KEAP1 的特点.这就是NRF2的NRF2.压力传感器是一种压力传感器.乌比基因结合酶的使用.

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