2. Academic Validation
  3. Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery

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

  • Cell Rep. 2020 Jun 30;31(13):107837. doi: 10.1016/j.celrep.2020.107837.
Carlos M Guardia 1,  Xiao-Feng Tan 2,  Tengfei Lian 2,  Mitra S Rana 3,  Wenchang Zhou 4,  Eric T Christenson 3,  Augustus J Lowry 3,  José D Faraldo-Gómez 4,  Juan S Bonifacino 5,  Jiansen Jiang 6,  Anirban Banerjee 7
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Unit on Structural and Chemical Biology of Membrane Proteins, 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.
  • 4 Theoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 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. Electronic address: juan.bonifacino@nih.gov.
  • 6 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. Electronic address: jiansen.jiang@nih.gov.
  • 7 Unit on Structural and Chemical Biology of Membrane Proteins, 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. Electronic address: anirban.banerjee@nih.gov.
PMID: 32610138 DOI: 10.1016/j.celrep.2020.107837
Abstract

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.

Keywords

ATG9A; autophagosome; autophagy; cryo-EM; membrane curvature; membrane morphology; membrane protein structure; membrane transport; molecular dynamics; transmembrane protein.

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