1-s2.0-S1097276522010176-main (1).pdf (7.47 MB)
ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation.
journal contributionposted on 2022-11-24, 10:48 authored by Alexander R van Vliet, George N Chiduza, Sarah L Maslen, Valerie E Pye, Dhira Joshi, Stefano De Tito, Harold BJ Jefferies, Evangelos Christodoulou, Chloë Roustan, Emma Punch, Javier H Hervás, Nicola O'Reilly, J Mark Skehel, Peter Cherepanov, Sharon A Tooze
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.
Crick (Grant ID: 10061, Grant title: Cherepanov FC001061) Crick (Grant ID: 10013, Grant title: STP Peptide Chemistry) Crick (Grant ID: 10011, Grant title: STP Proteomics) Crick (Grant ID: 10015, Grant title: STP Structural Biology) Crick (Grant ID: 10187, Grant title: Tooze FC001187)
AlphaFoldautophagosomeautophagyintegrative structure predictionlipid scramblaselipid transferAutophagosomesCryoelectron MicroscopyAutophagyBiological AssayLipidsTooze FC001187Cherepanov FC001061PRTPCSBNans, AndreaGeorge, RogerKunzelmann, SimoneWalker, PhilipCarzaniga, RaffaellaEM-ackLM-ackAnderson, KurtRenshaw, Matthew06 Biological Sciences11 Medical and Health SciencesDevelopmental Biology