Mechanistic Insights into Recognitions of Ubiquitin and Myosin VI by Autophagy Receptor TAX1BP1
Mechanistic Insights into Recognitions of Ubiquitin and Myosin VI by Autophagy Receptor TAX1BP1
复制标题
自噬受体 TAX1BP1 识别泛素和肌球蛋白 VI 的机制见解
DOI：
10.1016/j.jmb.2018.06.030
复制
发表时间：
2018
影响因子：
5.6
通讯作者：
Pan Lifeng
中科院分区：
文献类型：
--
作者：
Hu Shichen;Wang Yingli;Gong Yukang;Liu Jianping;Li Ying;Pan Lifeng
TAX1BP1是一种泛素结合接头，在天然免疫和选择性自噬中起着关键作用。在自噬过程中，TAX1BP1不仅可以作为自噬受体募集泛素化底物进行自噬降解，还可以作为Myosin VI货物衔接蛋白介导自噬体成熟。然而，TAX1BP1与泛素和肌球蛋白VI特异性相互作用的机制基础仍然难以捉摸。在这里，使用生化，NMR和结构分析，我们阐明了详细的结合机制，并揭示了TAX1BP1和泛素之间的相互作用的关键决定因素。此外，我们揭示了TAX1BP1的串联锌指和它们之间的构象刚性是TAX1BP1的肌球蛋白VI结合所需的，并且泛素和肌球蛋白VI在与TAX1BP1的结合中是相互排斥的。总的来说，我们的研究结果为TAX1BP1在选择性自噬中的双重功能提供了机制性见解。
TAX1BP1, a ubiquitin-binding adaptor, plays critical roles in the innate immunity and selective autophagy. During autophagy, TAX1BP1 may not only function as an autophagy receptor to recruit ubiquitylated substrates for autophagic degradation, but also serve as a Myosin VI cargo adaptor protein for mediating the maturation of autophagosome. However, the mechanistic basis underlying the specific interactions of TAX1BP1 with ubiquitin and Myosin VI remains elusive. Here, using biochemical, NMR and structural analyses, we elucidate the detailed binding mechanism and uncover the key determinants for the interaction between TAX1BP1 and ubiquitin. In addition, we reveal that both tandem zinc-fingers of TAX1BP1 and the conformational rigidity between them are required for the Myosin VI binding of TAX1BP1, and ubiquitin and Myosin VI are mutually exclusive in binding to TAX1BP1. Collectively, our findings provide mechanistic insights into the dual functions of TAX1BP1 in selective autophagy.