Fu Tao, Zhang Mingfang, Zhou Zixuan, Wu Ping, Peng Chao, Wang Yingli, Gong Xinyu, Li Ying, Wang Yaru, Xu Xiaolong, Li Miao, Shen Liqiang, Pan Lifeng
State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China.
National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China.
Sci Adv. 2021 Aug 13;7(33). doi: 10.1126/sciadv.abi6582. Print 2021 Aug.
The recruitment of Unc-51-like kinase and TANK-binding kinase 1 complexes is essential for Nuclear dot protein 52-mediated selective autophagy and relies on the specific association of NDP52, RB1-inducible coiled-coil protein 1, and Nak-associated protein 1 (5-azacytidine-induced protein 2, AZI2). However, the underlying molecular mechanism remains elusive. Here, we find that except for the NDP52 SKIP carboxyl homology (SKICH)/RB1CC1 coiled-coil interaction, the LC3-interacting region of NDP52 can directly interact with the RB1CC1 Claw domain, as that of NAP1 FIP200-binding region (FIR). The determined crystal structures of NDP52 SKICH/RB1CC1 complex, NAP1 FIR/RB1CC1 complex, and the related NAP1 FIR/Gamma-aminobutyric acid receptor-associated protein complex not only elucidate the molecular bases underpinning the interactions of RB1CC1 with NDP52 and NAP1 but also reveal that RB1CC1 Claw and Autophagy-related protein 8 family proteins are competitive in binding to NAP1 and NDP52. Overall, our findings provide mechanistic insights into the interactions of NDP52, NAP1 with RB1CC1 and ATG8 family proteins.
Unc-51样激酶和TANK结合激酶1复合物的募集对于核点蛋白52介导的选择性自噬至关重要，并且依赖于NDP52、RB1诱导的卷曲螺旋蛋白1和Nak相关蛋白1（5-氮杂胞苷诱导蛋白2，AZI2）的特异性结合。然而，其潜在的分子机制仍然不清楚。在这里，我们发现除了NDP52的SKIP羧基同源性（SKICH）/RB1CC1卷曲螺旋相互作用外，NDP52的LC3相互作用区域可以直接与RB1CC1爪结构域相互作用，就像NAP1的FIP200结合区域（FIR）一样。所确定的NDP52 SKICH/RB1CC1复合物、NAP1 FIR/RB1CC1复合物以及相关的NAP1 FIR/γ-氨基丁酸受体相关蛋白复合物的晶体结构不仅阐明了RB1CC1与NDP52和NAP1相互作用的分子基础，还揭示了RB1CC1爪结构域和自噬相关蛋白8家族蛋白在与NAP1和NDP52结合方面具有竞争性。总体而言，我们的研究结果为NDP52、NAP1与RB1CC1和ATG8家族蛋白的相互作用提供了机制性见解。
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