Abstract
ATG8 family proteins are evolutionary conserved ubiquitin-like modifiers, which become attached to the headgroup of the membrane lipid phosphatidylethanolamine in a process referred to as lipidation. This reaction is carried out analogous to the conjugation of ubiquitin to its target proteins, involving the E1-like ATG7, the E2-like ATG3 and the E3-like ATG12–ATG5–ATG16 complex, which determines the site of lipidation. ATG8 lipidation is a hallmark of autophagy where these proteins are involved in autophagosome formation, the fusion of autophagosomes with lysosomes and cargo selection. However, it has become evident that ATG8 lipidation also occurs in processes that are not directly related to autophagy. Here we discuss recent insights into the targeting of ATG8 lipidation in autophagy and other pathways with special emphasis on the recruitment and activation of the E3-like complex.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction The Atg[8] protein is a ubiquitin-like protein, which was identified in S. cerevisiae in the course of screens designed to discover genes required for the process of macroautophagy or the related cytoplasm-to-vacuole targeting (Cvt) pathway[1–3]
Unlike ubiquitin, which is conjugated to the lysine residues of target proteins via an isopeptide bond involving its C-terminal glycine residue, ATG8 proteins become attached to the amino headgroup of membrane lipids[11]
Structural studies of the yeast and human conjugation machineries showed that ATG8 proteins are first bound by the extreme C-terminal domain (ECTD) of ATG7 through hydrophobic and aromatic residues that insert deeply into the two hydrophobic pockets of the ubiquitinlike fold, in a mode similar to that described for LIR motifs[146]
Summary
Introduction TheAtg[8] protein is a ubiquitin-like protein, which was identified in S. cerevisiae in the course of screens designed to discover genes required for the process of macroautophagy (hereafter referred to as autophagy) or the related cytoplasm-to-vacuole targeting (Cvt) pathway[1–3]. In vitro ATG8 conjugation can occur in the absence of the E3-like complex, its presence vastly accelerates the reaction and it is essential for ATG8 lipidation in cells[12,23,25–27]. Other mechanisms to recruit the E3 to the site of autophagosome biogenesis via the ULK1/2 kinase complex[35–37], membrane binding[23,38,39] and cargo receptor interaction[40] do exist and will be discussed in detail below.
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