Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):E9792-E9801. doi: 10.1073/pnas.1811874115. Epub 2018 Sep 5.

Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A-WIPI4 complex.

Author information

1
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.
2
Department of Biology, Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich, 8093 Zurich, Switzerland.
3
Faculty of Science, University of Zurich, 8093 Zurich, Switzerland.
4
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037; glander@scripps.edu totomo@scripps.edu.

Abstract

Autophagy is an enigmatic cellular process in which double-membrane compartments, called "autophagosomes, form de novo adjacent to the endoplasmic reticulum (ER) and package cytoplasmic contents for delivery to lysosomes. Expansion of the precursor membrane phagophore requires autophagy-related 2 (ATG2), which localizes to the PI3P-enriched ER-phagophore junction. We combined single-particle electron microscopy, chemical cross-linking coupled with mass spectrometry, and biochemical analyses to characterize human ATG2A in complex with the PI3P effector WIPI4. ATG2A is a rod-shaped protein that can bridge neighboring vesicles through interactions at each of its tips. WIPI4 binds to one of the tips, enabling the ATG2A-WIPI4 complex to tether a PI3P-containing vesicle to another PI3P-free vesicle. These data suggest that the ATG2A-WIPI4 complex mediates ER-phagophore association and/or tethers vesicles to the ER-phagophore junction, establishing the required organization for phagophore expansion via the transfer of lipid membranes from the ER and/or the vesicles to the phagophore.

KEYWORDS:

ATG2; autophagy; chemical cross-linking coupled with mass spectrometry; membrane tethering; single-particle analysis

Comment in

PMID:
30185561
PMCID:
PMC6196511
[Available on 2019-04-16]
DOI:
10.1073/pnas.1811874115
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center