4 years ago

Structural analyses reveal that the ATG2A-WIPI4 complex functions as a membrane tether for autophagosome biogenesis

Otomo, K., Aebersold, R., S., Ohashi, A., C., Lander, Chowdhury, G. C., Leitner, Otomo, T.
Autophagy is an enigmatic cellular process in which double-membrane autophagic compartments form de novo adjacent to the ER, sequestering cytoplasmic contents within and delivering them to lysosomes. Expansion of the precursor membrane phagophore requires autophagy-related 2 (ATG2), which localizes to the phosphatidylinositol-3-phosphate (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 tip of ATG2A. WIPI4 binds to one of the tips, enabling the ATG2A-WIPI4 complex to tether a PI3P-containing vesicle with another PI3P-free vesicle. These data suggest that ATG2A mediates ER-phagophore association and/or tethers vesicles to the ER-phagophore junction, prerequisites for phagophore expansion via the transfer of lipid membranes from the ER and/or the vesicles to the phagophore.

Publisher URL: http://biorxiv.org/cgi/content/short/180315v1

DOI: 10.1101/180315

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