Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation
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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.
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Cites
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Mitochondrial degradation: Mitophagy and beyond
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Self-citation
- Authors
- Ren, X., Nguyen, T. N., Lam, W. K., Buffalo, C. Z., Lazarou, M., Yokom, A. L., & Hurley, J. H.
- Affiliations
- QB3 (US)
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Yokom, Adam L.
- Hurley, James H.
- ORCID
- Venue
- Science Advances
- Published
- 2023-02-17
- Volume
- 9
- Issue
- 7
- Pages
- eadg2997-eadg2997
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC9931213
- OpenAlex
- W4320896717
- Cited by
- 68
- References
- 7
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 20 · 2023: 16 · 2022: 1
- FWCI
- 13.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Science Advances (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- U.S. Department of Energy (76SF00515, DE–AC02–76SF00515, AC02‐76SF00515, P30-GM133894, DE-AC02-)
- Michael J. Fox Foundation for Parkinson's Research (ASAP-000350)
- National Institutes of Health (DE-AC02-76SF00515)
- Office of Science (AC02-76SF00515, DE-AC02-76SF0051 5, DE-AC02, P30GM133894, 76SF00515)
- Medical Research Council
- Australian Research Council (DP200100347)
- National Health and Medical Research Council (1106471)
- National Institute of General Medical Sciences (GM111730, DE-AC02-76SF00515, R01GM111730, P30GM133894)
- Basic Energy Sciences (DE-AC02, P30GM133894, 76SF00515, AC02-76SF00515, DE-AC-02-76SF00515)
- Biological and Environmental Research (DE- AC0276SF00515, P30GM133894)
- SLAC National Accelerator Laboratory (DEAC02−76SF00515, AC02‐76SF00515)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- ATG9A, ULK1 complex, mitophagy, autophagy initiation, PINK1/Parkin pathway, ATG13, ATG101, HORMA domain, protein-protein interaction, autophagosome formation, Parkinson's disease, crystal structure
- MeSH terms
- Autophagy-Related Proteins, Membrane Proteins, Protein Kinases, Ubiquitin-Protein Ligases, Mitophagy
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