Metamorphic proteins at the basis of human autophagy initiation and lipid transfer. Nguyen et al.

Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target a wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length seven-subunit human autophagy initiation super-complex, build on a core complex of ATG13-101 and ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to switch between distinct folds. The slow spontaneous metamorphic conversion is rate-limiting for the self-assembly of the super-complex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.

细胞自噬（Autophagy）是一类保守的细胞内降解途径，通过生成新生双层膜自噬体（autophagosome），将多种底物靶向运至溶酶体进行降解。在多细胞生物中，自噬起始过程需要内质网（ER）与新生自噬体之间及时形成接触位点。本研究报道了以ATG13-101与ATG9构成的核心复合物为基础的全长七亚基人类自噬起始超级复合物的体外重构（in vitro reconstitution）。该核心复合物的组装依赖于ATG13与ATG101在不同折叠构象间切换的稀有能力，其缓慢的自发构象转换是该超级复合物自组装的限速步骤。核心复合物与ATG2-WIPI4的相互作用可增强膜囊泡的拴留，并加速ATG9与ATG13-101介导的ATG2脂质转运过程。本研究揭示了自噬接触位点的分子基础，以及ATG13-101的构象重塑所介导的组装机制，该机制可在时空维度精准调控自噬体的生物发生。