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TitleATG9B is a tissue-specific homotrimeric lipid scramblase that can compensate for ATG9A.
Journal, issue, pagesAutophagy, Vol. 20, Issue 3, Page 557-576, Year 2024
Publish dateNov 17, 2023
AuthorsGeorge N Chiduza / Acely Garza-Garcia / Eugenia Almacellas / Stefano De Tito / Valerie E Pye / Alexander R van Vliet / Peter Cherepanov / Sharon A Tooze /
PubMed AbstractMacroautophagy/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.
External linksAutophagy / PubMed:37938170 / PubMed Central
MethodsEM (single particle)
Resolution4.2 - 4.6 Å
Structure data

17789

8poe

EMDB-17789, PDB-8poe:
Structure of tissue-specific lipid scramblase ATG9B homotrimer, refined with C3 symmetry applied
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-17790: Structure of tissue-specific lipid scramblase ATG9B homotrimer, refined without imposing symmetry
Method: EM (single particle) / Resolution: 4.6 Å

Source
  • homo sapiens (human)
KeywordsLIPID TRANSPORT / membrane protein / lipid scramblase / autophagy / phagopore / lipid transporter / Atg9 / Atg9B

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