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Abstract

Lipidation of Atg8-family ubiquitin-like proteins (UBLs) plays important roles in macroautophagy/autophagy. This process is catalyzed by an E1-E2-E3 trienzyme cascade, in which an E1 enzyme, Atg7, directs Atg8 to its E2 enzyme, Atg3, forming a thioester bond-linked Atg3 similar to Atg8 intermediate; then the composite E3, Atg12-Atg5-Atg16, interacts with the Atg3 similar to Atg8 intermediate and promotes Atg8 transfer from the catalytic cysteine of Atg3 to the head group of phosphatidylethanolamine (PE) lipids. Despite progress that has been made toward understanding the Atg8 lipidation pathway, the molecular mechanism of Atg3 as it orchestrates between the E1 and E3 remains unclear. Here we summarize our recent work reporting an element in Atg3, termed the E1, E2, and E3-interacting region (E123IR), is an allosteric switch: in the absence of other binding partners, the E123IR restrains Atg3 ' s catalytic loop, while the E1 or E3 enzyme directly binds this region to remove this brace and thereby conformationally activate Atg3 to elicit Atg8 lipidation in vitro and in vivo.