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Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation
Open accessPreprint — published as 10.1126/sciadv.adg2997 · Paper page
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, ATG9A, and components of the 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 C-terminal tail bound to the ATG13:ATG101 HORMA dimer, which is part of the ULK1 complex. We term the interacting portion of the extreme C-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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Highly accurate protein structure prediction with AlphaFold
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Metadata
- 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 Lee
- Hurley, James H.
- ORCID
- Venue
- Science Advances
- Publisher
- openRxiv
- Published
- 2022-07-13
- Volume
- 9
- Issue
- 7
- Pages
- eadg2997-eadg2997
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC9931213
- OpenAlex
- W4320896717
- Cited by
- 68
- References
- 1
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 20 · 2023: 16 · 2022: 1
- FWCI
- 13.32
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Clinical 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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