Structural and biochemical advances on the recruitment of the autophagy-initiating ULK and TBK1 complexes by autophagy receptor NDP52

Tao Fu; Mingfang Zhang; Zixuan Zhou; Ping Wu; Chao Peng; Yingli Wang; Xinyu Gong; Ying Li; Yaru Wang; Xiaolong Xu; Miao Li; Liqiang Shen; Lifeng Pan

doi:10.1126/sciadv.abi6582

Structural and biochemical advances on the recruitment of the autophagy-initiating ULK and TBK1 complexes by autophagy receptor NDP52

Sci Adv. 2021 Aug 13;7(33):eabi6582. doi: 10.1126/sciadv.abi6582. Print 2021 Aug.

Authors

Tao Fu¹, Mingfang Zhang¹, Zixuan Zhou¹, Ping Wu², Chao Peng², Yingli Wang¹, Xinyu Gong¹, Ying Li¹, Yaru Wang¹, Xiaolong Xu¹, Miao Li³, Liqiang Shen³, Lifeng Pan^{4

3}

Affiliations

¹ 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.
² National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China.
³ School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, China.
⁴ 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. panlf@sioc.ac.cn.

Abstract

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.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).