An N-terminal conserved region in human Atg3 couples membrane curvature sensitivity to conjugase activity during autophagy

Yansheng Ye, Erin R. Tyndall, Bui Van, Zhenyuan Tang, Yan Shen, Xuejun Jiang, John M. Flanagan, Hong-Gang Wang () and Fang Tian ()
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Yansheng Ye: Penn State College of Medicine
Erin R. Tyndall: Penn State College of Medicine
Bui Van: Penn State College of Medicine
Zhenyuan Tang: Penn State College of Medicine
Yan Shen: National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health
Xuejun Jiang: Memorial Sloan Kettering Cancer Center
John M. Flanagan: Penn State College of Medicine
Hong-Gang Wang: Penn State College of Medicine
Fang Tian: Penn State College of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation. Here, we have demonstrated that an N-terminal conserved region of human Atg3 (hAtg3) communicates information from the N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore, to the C-terminally located catalytic core for LC3–PE conjugation. Mutations in the putative communication region greatly reduce or abolish the ability of hAtg3 to catalyze this conjugation in vitro and in vivo, and alter the membrane-bound conformation of the wild-type protein, as reported by NMR. Collectively, our results demonstrate that the N-terminal conserved region of hAtg3 works in concert with its geometry-selective AH to promote LC3–PE conjugation only on the target membrane, and substantiate the concept that highly curved membranes drive spatial regulation of the autophagosome biogenesis during autophagy.

Date: 2021
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DOI: 10.1038/s41467-020-20607-0

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