Metamorphic proteins at the basis of human autophagy initiation and lipid transfer

Nguyen, A.; Lugarini, F.; David, C.; Hosani, P.; Knotkova, B.; Patel, A.; Parfentev, I.; Friedrich, A.; Urlaub, H.; Meinecke, M.; Stork, B.; Faesen, A.

doi:10.1101/2022.09.21.508836

bioRxiv · 10.1101/2022.09.21.508836

Metamorphic proteins at the basis of human autophagy initiation and lipid transfer

Nguyen, A.·Lugarini, F.·David, C.·Hosani, P.·Knotkova, B.·Patel, A.·Parfentev, I.·Friedrich, A.·Urlaub, H.·Meinecke, M.·Stork, B.·Faesen, A.

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Abstract

Autophagy is a conserved intracellular degradation pathway that uses de novo doublemembrane vesicle (autophagosome) formation to target a wide range of cytoplasmic material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length sevensubunit human autophagy initiation supercomplex and found at its core ATG13-101 and transmembrane protein ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to adopt topologically distinct folds. The slow spontaneous conversion between folds creates a rate-limiting step to regulate selfassembly of the super-complex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.

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Nguyen, A., Lugarini, F., David, C., Hosani, P., Knotkova, B., Patel, A., Parfentev, I., Friedrich, A., Urlaub, H., Meinecke, M., Stork, B., Faesen, A.. 2022-09-21. Metamorphic proteins at the basis of human autophagy initiation and lipid transfer. https://doi.org/10.1101/2022.09.21.508836

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