Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets’ degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate.

中文翻译：

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在氧化应激下，两种 F-box 蛋白识别 BACH1 四级结构 degrons


泛素依赖性蛋白水解以高底物特异性调节多种细胞功能，这取决于泛素 E3 连接酶解码靶标降解信号（即 degrons）的能力。在这里，我们表明 BACH1 是抗氧化反应基因的转录抑制因子，在其同型二聚体 BTB 结构域的四级结构中加密了两个不同的非常规 degrons。这两个 degrons 都被氧化应激功能化，并被两个互补的 E3 破译。FBXO22 识别由 BACH1 BTB 结构域二聚体界面构建的 degron，在氧化应激从染色质中释放 BACH1 后，该界面被转录共阻遏蛋白揭蔽。当该 degron 因氧化而受损时，由其不稳定的 BTB 二聚体表现出的第二个 BACH1 degron 被一对 FBXL17 蛋白探测，该蛋白将底物重塑为 E3 结合的单体以进行泛素化。我们的研究结果强调了蛋白质降解信号的多维性以及靶向相同底物的不同泛素连接酶的功能互补性。