ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation
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Alexander Van Vliet George Chiduza Sarah L Maslen Val Pye Dhira Joshi Stefano De Tito Harold Jefferies Evangelos Christodoulou Chloe Roustan Emma Punch Javier Hervas Nicola O'Reilly Mark Skehel Peter Cherepanov Sharon ToozeAbstract
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.
Journal details
Journal
Molecular Cell
Volume
82
Issue number
22
Pages
4324-4339.e8
Available online
Publication date
Full text links
Publisher website (DOI)
10.1016/j.molcel.2022.10.017
Europe PubMed Central
36347259
Pubmed
36347259
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