Section on Intracellular Protein Trafficking, Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2020 Jun 30;31(13):107837. doi: 10.1016/j.celrep.2020.107837.
Autophagy is a catabolic process involving capture of cytoplasmic materials into double-membraned autophagosomes that subsequently fuse with lysosomes for degradation of the materials by lysosomal hydrolases. One of the least understood components of the autophagy machinery is the transmembrane protein ATG9. Here, we report a cryoelectron microscopy structure of the human ATG9A isoform at 2.9-Å resolution. The structure reveals a fold with a homotrimeric domain-swapped architecture, multiple membrane spans, and a network of branched cavities, consistent with ATG9A being a membrane transporter. Mutational analyses support a role for the cavities in the function of ATG9A. In addition, structure-guided molecular simulations predict that ATG9A causes membrane bending, explaining the localization of this protein to small vesicles and highly curved edges of growing autophagosomes.
自噬是一种涉及细胞质物质捕获到双层膜自噬体的分解代谢过程，随后自噬体与溶酶体融合，通过溶酶体水解酶降解物质。自噬机制中了解最少的成分之一是跨膜蛋白 ATG9。在这里，我们报告了人类 ATG9A 同工型的 2.9-Å 分辨率的冷冻电镜结构。该结构揭示了一个具有同源三聚体结构域交换结构、多个膜跨度和分支腔网络的折叠，这与 ATG9A 作为膜转运蛋白一致。突变分析支持腔在 ATG9A 功能中的作用。此外，结构导向的分子模拟预测 ATG9A 会引起膜弯曲，这解释了该蛋白定位于小泡和正在生长的自噬体的高曲率边缘。
