ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation.
Description
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, while 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 cryo-electron microscopy, we propose a molecular model of the ATG9A-2A complex. Using this integrative structure modelling approach, we identify several interfaces mediating ATG9A-2A interaction which 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.