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Author Spotlight: Imaging ATG9A, a Multi-Spanning Membrane Protein
Published on: June 16, 2023
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Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation
Xuefeng Ren1,2,3, Thanh N Nguyen3,4,5,6, Wai Kit Lam3,4,5,6
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Science Advances
|February 15, 2023
Summary
Researchers elucidated the structural basis of autophagy initiation, revealing how ATG9A interacts with the ULK1 complex. This finding is crucial for understanding mitophagy in Parkinson's disease.
Area of Science:
- Cellular Biology
- Structural Biology
- Neuroscience
Background:
- Autophagy is essential for cellular homeostasis and is implicated in neurodegenerative diseases like Parkinson's.
- The Unc-51-like autophagy activating kinase (ULK1) complex initiates autophagy.
- Autophagy-related protein 9A (ATG9A) is the only known transmembrane protein in the autophagy machinery, but its interaction with the ULK1 complex is poorly understood.
Purpose of the Study:
- To determine the structural basis of the interaction between ATG9A and the ULK1 complex.
- To provide a missing link in the structural map of autophagy initiation.
Main Methods:
- X-ray crystallography was used to determine the 2.4-Å structure of the ternary complex.
- The structure reveals the binding interface between ATG9A's carboxyl-terminal tail and the ATG13:ATG101 HORMA dimer.
Main Results:
- The structure identified the "HORMA dimer-interacting region" (HDIR) on ATG9A.
- HDIR binds to the HORMA domain of ATG101 via β sheet complementation within a cleft at the ATG13:ATG101 interface.
- Disruption of this interaction in cells impaired PINK1/Parkin-dependent mitophagy.
Conclusions:
- The study reveals the molecular mechanism by which ATG9A integrates into the ULK1 complex.
- This structural insight is critical for understanding the PINK1/Parkin mitophagy pathway and its role in Parkinson's disease.
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