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  Scaffolding the cup-shaped double membrane in autophagy

Bahrami, A. H., Lin, M. G., Ren, X., Hurley, J. H., & Hummer, G. (2017). Scaffolding the cup-shaped double membrane in autophagy. PLoS Computational Biology, 13(10): e1005817. doi:10.1371/journal.pcbi.1005817.

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 Creators:
Bahrami, Amir Houshang1, Author           
Lin, Mary G.2, Author
Ren, Xuefeng2, Author
Hurley, James H.2, 3, Author
Hummer, Gerhard1, 4, Author                 
Affiliations:
1Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Max Planck Society, ou_2068292              
2Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, California, United States of America, ou_persistent22              
3Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, ou_persistent22              
4Institute for Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany, ou_persistent22              

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 Abstract: Autophagy is a physiological process for the recycling and degradation of cellular materials. Forming the autophagosome from the phagophore, a cup-shaped double-membrane vesicle, is a critical step in autophagy. The origin of the cup shape of the phagophore is poorly understood. In yeast, fusion of a small number of Atg9-containing vesicles is considered a key step in autophagosome biogenesis, aided by Atg1 complexes (ULK1 in mammals) localized at the preautophagosomal structure (PAS). In particular, the S-shaped Atg17-Atg31-Atg29 subcomplex of Atg1 is critical for phagophore nucleation at the PAS. To study this process, we simulated membrane remodeling processes in the presence and absence of membrane associated Atg17. We show that at least three vesicles need to fuse to induce the phagophore shape, consistent with experimental observations. However, fusion alone is not sufficient. Interactions with 34-nm long, S-shaped Atg17 complexes are required to overcome a substantial kinetic barrier in the transition to the cup-shaped phagophore. Our finding rationalizes the recruitment of Atg17 complexes to the yeast PAS, and their unusual shape. In control simulations without Atg17, with weakly binding Atg17, or with straight instead of S-shaped Atg17, the membrane shape transition did not occur. We confirm the critical role of Atg17-membrane interactions experimentally by showing that mutations of putative membrane interaction sites result in reduction or loss of autophagic activity in yeast. Fusion of a small number of vesicles followed by Atg17-guided membrane shape-remodeling thus emerges as a viable route to phagophore formation.

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Language(s): eng - English
 Dates: 2017-05-312017-10-092017-10-24
 Publication Status: Published online
 Pages: 29
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1371/journal.pcbi.1005817
 Degree: -

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Title: PLoS Computational Biology
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 13 (10) Sequence Number: e1005817 Start / End Page: - Identifier: ISSN: 1553-734X
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000017180_1