Multiple structural rearrangements mediated by high-plasticity regions in Atg3 are key for efficient conjugation of Atg8 to PE during autophagy.

The Atg3 protein is highly homologous from yeast to human. Atg3 functions as an E2-like enzyme promoting conjugation of Atg8-family proteins to phosphatidylethanolamine (PE), a lipid molecule embedded in the growing phagophore membrane during stress-induced autophagy. Over the last decade, Atg3 became one of the most explored autophagy proteins, resulting in observations that provided specific insights into the structural mechanisms of its function. In this article, we describe a recent study by Ye et al. that reveals, using the human ATG3, how the membrane binding capability of the enzyme is tightly linked to its conjugation activity. We summarize the current knowledge on important mechanisms that involve protein-protein or protein-membrane interactions of Atg3 and that ultimately lead to efficient Atg8-PE conjugation. AH: amphipathic helix; FR: flexible region; HR: handle region; NMR: nuclear magnetic resonance.