Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
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DOI：
10.1016/j.molcel.2006.01.013
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发表时间：
2006-03-03
期刊：
影响因子：
16
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Padmanabhan, B;Tong, KI;Yamamoto, M
Nrf 2调节细胞氧化应激反应，而Keapl通过其分子相互作用抑制Nrf 2。为了阐明Keapl和Nrf 2相互作用的分子机制，我们解析了小鼠Keapl的Kelch/DGR和CTR结构域的六叶β螺旋桨晶体结构，并揭示了广泛的间隙和间隙内氢键维持了Keapl与Nrf 2的结构完整性和适当的缔合。含有Nrf 2的ETGE基序的肽通过与保守的精氨酸残基的静电相互作用在底侧的中央腔的入口处结合Keap 1的β推进器。我们在人肺癌细胞中发现了一个体细胞突变和一个基因变异，将DGR结构域中的甘氨酸变为半胱氨酸，引入了局部构象变化，降低了Keap 1对Nrf 2的亲和力。这些结果为Keapl功能的丧失和Nrf 2功能的获得提供了结构基础。
Nrf2 regulates the cellular oxidative stress response, whereas Keapl represses Nrf2 through its molecular interaction. To elucidate the molecular mechanism of the Keapl and Nrf2 interaction, we resolved the six-bladed beta propeller crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed that extensive inter- and intrablacle hydrogen bonds maintain the structural integrity and proper association of Keapl with Nrf2. A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues. We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2. These results provide a structural basis for the loss of Keapl function and gain of Nrf2 function.