Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy

• DOI: 10.1016/j.molcel.2015.11.019
• Publication Date: 2015-12-18T02:34:53Z
• Authors: Fan Wu; Yasunori Watanabe; Xiang-Yang Guo; Xin Qi; Peng Wang; Hong-Yu Zhao; Zheng Wang; Yuko Fujioka; Hui Zhang; Jin-Qi Ren; Tian-Cheng Fang; Yu-Xian Shen; Wei Feng; Jun-Jie Hu; Nobuo N. Noda; Hong Zhang
• Keywords: ATG8

Multicellular organisms have multiple homologs of the yeast ATG8 gene, but the differential roles of these homologs in autophagy during development remain largely unknown. Here we investigated structure/function relationships in the two C. elegans Atg8 homologs, LGG-1 and LGG-2. lgg-1 is essential for degradation of protein aggregates, while lgg-2 has cargo-specific and developmental-stage-specific roles in aggregate degradation. Crystallography revealed that the N-terminal tails of LGG-1 and LGG-2 adopt the closed and open form, respectively. LGG-1 and LGG-2 interact differentially with autophagy substrates and Atg proteins, many of which carry a LIR motif. LGG-1 and LGG-2 have structurally distinct substrate binding pockets that prefer different residues in the interacting LIR motif, thus influencing binding specificity. Lipidated LGG-1 and LGG-2 possess distinct membrane tethering and fusion activities, which may result from the N-terminal differences. Our study reveals the differential function of two ATG8 homologs in autophagy during C. elegans development.