ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation

ATG9A and ATG2A are essential core members of the autophagy machinery. ATG9A is a lipid scramblase that allows equilibration of lipids across a membrane bilayer, whereas ATG2A facilitates lipid flow between tethered membranes. Although both have been functionally linked during the formation of autop...

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Published in:Molecular cell 2022-11, Vol.82 (22), p.4324-4339.e8
Main Authors: van Vliet, Alexander R., Chiduza, George N., Maslen, Sarah L., Pye, Valerie E., Joshi, Dhira, De Tito, Stefano, Jefferies, Harold B.J., Christodoulou, Evangelos, Roustan, Chloë, Punch, Emma, Hervás, Javier H., O’Reilly, Nicola, Skehel, J. Mark, Cherepanov, Peter, Tooze, Sharon A.
Format: Article
Language:English
Subjects:
AlphaFold
autophagosome
Autophagosomes
Autophagy
Biological Assay
Cryoelectron Microscopy
integrative structure prediction
lipid scramblase
lipid transfer
Lipids
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Summary:ATG9A and ATG2A are essential core members of the autophagy machinery. ATG9A is a lipid scramblase that allows equilibration of lipids across a membrane bilayer, whereas ATG2A facilitates lipid flow between tethered membranes. Although both have been functionally linked during the formation of autophagosomes, the molecular details and consequences of their interaction remain unclear. By combining data from peptide arrays, crosslinking, and hydrogen-deuterium exchange mass spectrometry together with cryoelectron microscopy, we propose a molecular model of the ATG9A-2A complex. Using this integrative structure modeling approach, we identify several interfaces mediating ATG9A-2A interaction that would allow a direct transfer of lipids from ATG2A into the lipid-binding perpendicular branch of ATG9A. Mutational analyses combined with functional activity assays demonstrate their importance for autophagy, thereby shedding light on this protein complex at the heart of autophagy. [Display omitted] •ATG9A and ATG2A form a heterotetrameric complex•HDX and CXL-MS reveal intricate interaction interface between ATG9A and ATG2A•Disrupting the ATG9A-ATG2A complex disrupts autophagic flux•Lipid transfer tunnel of ATG2A binds proximal to the perpendicular branch of ATG9A A critical aspect of autophagy is the membrane growth of the phagophore, a process that is still elusive. Here, we show that complex formation by the scramblase ATG9A and lipid transfer protein ATG2A is required for autophagy and characterize their interaction interface using structural mass spectrometry and EM techniques.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2022.10.017