Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery
Summary: 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 transmemb...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-06-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720308184 |
| _version_ | 1818532739332177920 |
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| author | Carlos M. Guardia Xiao-Feng Tan Tengfei Lian Mitra S. Rana Wenchang Zhou Eric T. Christenson Augustus J. Lowry José D. Faraldo-Gómez Juan S. Bonifacino Jiansen Jiang Anirban Banerjee |
| author_facet | Carlos M. Guardia Xiao-Feng Tan Tengfei Lian Mitra S. Rana Wenchang Zhou Eric T. Christenson Augustus J. Lowry José D. Faraldo-Gómez Juan S. Bonifacino Jiansen Jiang Anirban Banerjee |
| author_sort | Carlos M. Guardia |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-12-11T17:49:27Z |
| format | Article |
| id | doaj.art-c2bbdec4aa9f4899827cc7fabd64a7b9 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T17:49:27Z |
| publishDate | 2020-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c2bbdec4aa9f4899827cc7fabd64a7b92022-12-22T00:56:16ZengElsevierCell Reports2211-12472020-06-013113107837Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy MachineryCarlos M. Guardia0Xiao-Feng Tan1Tengfei Lian2Mitra S. Rana3Wenchang Zhou4Eric T. Christenson5Augustus J. Lowry6José D. Faraldo-Gómez7Juan S. Bonifacino8Jiansen Jiang9Anirban Banerjee10Section 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, USALaboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAUnit 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, USATheoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USAUnit 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, USAUnit 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, USATheoretical Molecular Biophysics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USASection 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; Corresponding authorLaboratory of Membrane Proteins and Structural Biology, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding authorUnit 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720308184ATG9Aautophagosomeautophagycryo-EMmolecular dynamicstransmembrane protein |
| spellingShingle | Carlos M. Guardia Xiao-Feng Tan Tengfei Lian Mitra S. Rana Wenchang Zhou Eric T. Christenson Augustus J. Lowry José D. Faraldo-Gómez Juan S. Bonifacino Jiansen Jiang Anirban Banerjee Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery Cell Reports ATG9A autophagosome autophagy cryo-EM molecular dynamics transmembrane protein |
| title | Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery |
| title_full | Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery |
| title_fullStr | Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery |
| title_full_unstemmed | Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery |
| title_short | Structure of Human ATG9A, the Only Transmembrane Protein of the Core Autophagy Machinery |
| title_sort | structure of human atg9a the only transmembrane protein of the core autophagy machinery |
| topic | ATG9A autophagosome autophagy cryo-EM molecular dynamics transmembrane protein |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720308184 |
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