Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery

• Published in: Cell reports (Cambridge) 2020-06, Vol.31 (13), p.107837-107837, Article 107837
• Main Authors: Guardia, Carlos M., Tan, Xiao-Feng, Lian, Tengfei, Rana, Mitra S., Zhou, Wenchang, Christenson, Eric T., Lowry, Augustus J., Faraldo-Gómez, José D., Bonifacino, Juan S., Jiang, Jiansen, Banerjee, Anirban
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; ATG9A; autophagosome; Autophagy; Autophagy-Related Proteins - chemistry; Autophagy-Related Proteins - metabolism; Autophagy-Related Proteins - ultrastructure; cryo-EM; Cryoelectron Microscopy; HEK293 Cells; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers - chemistry; membrane curvature; membrane morphology; membrane protein structure; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Membrane Proteins - ultrastructure; membrane transport; molecular dynamics; Molecular Dynamics Simulation; Mutagenesis - genetics; Phosphatidylcholines - chemistry; Protein Domains; Protein Multimerization; Protein Structure, Secondary; Protein Subunits - chemistry; Protein Subunits - metabolism; transmembrane protein; Vesicular Transport Proteins - chemistry; Vesicular Transport Proteins - metabolism; Vesicular Transport Proteins - ultrastructure
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •The transmembrane autophagy protein ATG9A is a domain-swapped homotrimer•Each ATG9A protomer comprises four transmembrane domains•The ATG9A homotrimer exhibits an internal network of branched cavities•Molecular dynamics simulations show that ATG9A trimers deform membranes Guardia et al. report a high-resolution cryo-EM structure of human ATG9A, the only transmembrane protein of the core autophagy machinery. The structure shows that ATG9A is a domain-swapped homotrimer with a complex network of internal cavities. Structure-based computational simulations predict that ATG9A has membrane-bending properties.