Insights on autophagosome–lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5
| Autor: | Thanh Ngoc Nguyen, Calvin K. Yip, Michael Lazarou, Yiu Wing Sunny Cheung, Michael Gong, Samuel Chan, Sung Eun Nam |
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| Rok vydání: | 2021 |
| Předmět: |
Autophagosome
Protein Conformation Vesicular Transport Proteins Autophagy-Related Proteins Medicine (miscellaneous) Cellular homeostasis Membrane trafficking 0302 clinical medicine Mitophagy Sf9 Cells Biology (General) Late endosome 0303 health sciences Protein Stability Mitochondria Cell biology Protein Transport medicine.anatomical_structure General Agricultural and Biological Sciences Microtubule-Associated Proteins Protein Binding QH301-705.5 GABARAP PINK1 Biology Cataract Article General Biochemistry Genetics and Molecular Biology Structure-Activity Relationship 03 medical and health sciences Lysosome Electron microscopy Autophagy medicine Animals Humans Genetic Predisposition to Disease Protein Interaction Domains and Motifs Adaptor Proteins Signal Transducing X-ray crystallography 030304 developmental biology Autophagosomes Autophagy-Related Protein 8 Family Mutation Proteolysis Agenesis of Corpus Callosum Apoptosis Regulatory Proteins Lysosomes 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | Communications Biology Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-021-01830-x |
| Popis: | Pivotal to the maintenance of cellular homeostasis, macroautophagy (hereafter autophagy) is an evolutionarily conserved degradation system that involves sequestration of cytoplasmic material into the double-membrane autophagosome and targeting of this transport vesicle to the lysosome/late endosome for degradation. EPG5 is a large-sized metazoan protein proposed to serve as a tethering factor to enforce autophagosome–lysosome/late endosome fusion specificity, and its deficiency causes a severe multisystem disorder known as Vici syndrome. Here, we show that human EPG5 (hEPG5) adopts an extended “shepherd’s staff” architecture. We find that hEPG5 binds preferentially to members of the GABARAP subfamily of human ATG8 proteins critical to autophagosome–lysosome fusion. The hEPG5–GABARAPs interaction, which is mediated by tandem LIR motifs that exhibit differential affinities, is required for hEPG5 recruitment to mitochondria during PINK1/Parkin-dependent mitophagy. Lastly, we find that the Vici syndrome mutation Gln336Arg does not affect the hEPG5’s overall stability nor its ability to engage in interaction with the GABARAPs. Collectively, results from our studies reveal new insights into how hEPG5 recognizes mature autophagosome and establish a platform for examining the molecular effects of Vici syndrome disease mutations on hEPG5. Nam and Cheung et al. describe the structural and biochemical characterization of human autophagy factor EPG5 that functions in autophagosome–lysosome tethering. They show that hEPG5 adopts an extended shepherd’s staff architecture, binds preferentially to GABARAP proteins, and is recruited to mitochondria during mitophagy. |
| Databáze: | OpenAIRE |
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