RT Journal Article
SR Electronic
T1 Human ATG3 contains a non-canonical LIR motif crucial for its enzymatic activity in autophagy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.08.02.502437
DO 10.1101/2022.08.02.502437
A1 Jakob Farnung
A1 Matthias Muhar
A1 Jin Rui Liang
A1 Kateryna A. Tolmachova
A1 Roger M. Benoit
A1 Jacob E. Corn
A1 Jeffrey W. Bode
YR 2022
UL http://biorxiv.org/content/early/2022/08/02/2022.08.02.502437.abstract
AB Macroautophagy is one of two major degradation systems in eukaryotic cells. Regulation and control of autophagy is often achieved through the presence of short peptide sequences called LC3 interacting regions (LIR) in autophagy-involved proteins. Using a combination of new protein-derived activity-based probes, protein modelling and X-ray crystallography, we identified a non-canonical LIR motif in the human E2 enzyme responsible for LC3 lipidation, ATG3. The LIR motif is present in the flexible region of ATG3 and adopts an uncommon β-sheet structure binding to the backside of LC3. We show that the β-sheet conformation is crucial for its interaction with LC3. In cellulo studies provide evidence that LIRATG3 is required for LC3 lipidation and ATG3∼LC3 thioester formation. Removal of LIRATG3 negatively impacts the rate of thioester transfer from ATG7 to ATG3.Competing Interest StatementThe authors have declared no competing interest.