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-Structure paper
タイトル | ATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A. |
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ジャーナル・号・ページ | Autophagy, Vol. 20, Issue 3, Page 557-576, Year 2024 |
掲載日 | 2023年11月17日 |
著者 | George N Chiduza / Acely Garza-Garcia / Eugenia Almacellas / Stefano De Tito / Valerie E Pye / Alexander R van Vliet / Peter Cherepanov / Sharon A Tooze / |
PubMed 要旨 | Macroautophagy/autophagy is a fundamental aspect of eukaryotic biology, and the autophay-related protein ATG9A is part of the core machinery facilitating this process. In addition to ATG9A ...Macroautophagy/autophagy is a fundamental aspect of eukaryotic biology, and the autophay-related protein ATG9A is part of the core machinery facilitating this process. In addition to ATG9A vertebrates encode ATG9B, a poorly characterized paralog expressed in a subset of tissues. Herein, we characterize the structure of human ATG9B revealing the conserved homotrimeric quaternary structure and explore the conformational dynamics of the protein. Consistent with the experimental structure and computational chemistry, we establish that ATG9B is a functional lipid scramblase. We show that ATG9B can compensate for the absence of ATG9A in starvation-induced autophagy displaying similar subcellular trafficking and steady-state localization. Finally, we demonstrate that ATG9B can form a heteromeric complex with ATG2A. By establishing the molecular structure and function of ATG9B, our results inform the exploration of niche roles for autophagy machinery in more complex eukaryotes and reveal insights relevant across species. ATG: autophagy related; CHS: cholesteryl hemisuccinate; cryo-EM: single-particle cryogenic electron microscopy; CTF: contrast transfer function: CTH: C- terminal α helix; FSC: fourier shell correlation; HDIR: HORMA domain interacting region; LMNG: lauryl maltose neopentyl glycol; MD: molecular dynamics simulations; MSA: multiple sequence alignment; NBD-PE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl ammonium salt); POPC: palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; RBG: repeating beta groove domain; RMSD: root mean square deviation; SEC: size-exclusion chromatography; TMH: transmembrane helix. |
リンク | Autophagy / PubMed:37938170 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 4.2 - 4.6 Å |
構造データ | EMDB-17789, PDB-8poe: EMDB-17790: Structure of tissue-specific lipid scramblase ATG9B homotrimer, refined without imposing symmetry |
由来 |
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キーワード | LIPID TRANSPORT / membrane protein (膜タンパク質) / lipid scramblase / autophagy (オートファジー) / phagopore / lipid transporter / Atg9 / Atg9B |