Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation
- Author(s)
- Ren, X; Nguyen, TN; Lam, WK; Buffalo, CZ; Lazarou, M; Yokom, AL; Hurley, JH;
- Details
- Publication Year 2023-02-15,Volume 9,Issue #7,Page eadg2997
- Journal Title
- Science Advances
- Abstract
- The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in the PINK1- and Parkin-dependent mitophagy pathway implicated in Parkinson's disease. The structural interaction between the sole transmembrane autophagy protein, autophagy-related protein 9A (ATG9A), and components of the Unc-51-like autophagy activating kinase (ULK1) complex is one of the major missing links needed to complete a structural map of autophagy initiation. We determined the 2.4-Å x-ray crystallographic structure of the ternary structure of ATG9A carboxyl-terminal tail bound to the ATG13:ATG101 Hop1/Rev7/Mad2 (HORMA) dimer, which is part of the ULK1 complex. We term the interacting portion of the extreme carboxyl-terminal part of the ATG9A tail the "HORMA dimer-interacting region" (HDIR). This structure shows that the HDIR binds to the HORMA domain of ATG101 by β sheet complementation such that the ATG9A tail resides in a deep cleft at the ATG13:ATG101 interface. Disruption of this complex in cells impairs damage-induced PINK1/Parkin mitophagy mediated by the cargo receptor NDP52.
- Publisher
- AAAS
- Research Division(s)
- Ubiquitin Signalling
- PubMed ID
- 36791199/
- Publisher's Version
- https://doi.org/10.1126/sciadv.adg2997
- Open Access at Publisher's Site
https://doi.org/10.1126/sciadv.adg299- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-02-27 10:36:18
Last Modified: 2023-03-06 01:32:24