Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation.
Sci Adv
; 9(7): eadg2997, 2023 02 15.
Article
em En
| MEDLINE
| ID: mdl-36791199
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 ATG13ATG101 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 ß sheet complementation such that the ATG9A tail resides in a deep cleft at the ATG13ATG101 interface. Disruption of this complex in cells impairs damage-induced PINK1/Parkin mitophagy mediated by the cargo receptor NDP52.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Mitofagia
/
Proteínas de Membrana
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article