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Structural basis of target recognition by Atg8/LC3 during selective autophagy

机译：选择性自噬过程中Atg8 / LC3识别靶标的结构基础

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摘要

Autophagy is a non-selective bulk degradation process in which isolation membranes enclose a portion of cytoplasm to form double-membrane vesicles, called autophagosomes, and deliver their inner constituents to the lytic compartments. Recent studies have also shed light on another mode of autophagy that selectively degrades various targets. Yeast Atg8 and its mammalian homologue LC3 are ubiquitin-like modifiers that are localized on isolation membranes and play crucial roles in the formation of autophagosomes. These proteins are also involved in selective incorporation of specific cargo molecules into autophagosomes, in which Atg8 and LC3 interact with Atg19 and p62, receptor proteins for vacuolar enzymes and disease-related protein aggregates, respectively. Using X-ray crystallography and NMR, we herein report the structural basis for Atg8-Atg19 and LC3-p62 interactions. Remarkably, Atg8 and LC3 were shown to interact with Atg19 and p62, respectively, in a quite similar manner: they recognized the side-chains of Trp and Leu in a four-amino acid motif, WXXL, in Atg19 and p62 using hydrophobic pockets conserved among Atg8 homologues. Together with mutational analyses, our results show the fundamental mechanism that allows Atg8 homologues, in association with WXXL-containing proteins, to capture specific cargo molecules, thereby endowing isolation membranes and/or their assembly machineries with target selectivity.
机译：自噬是一种非选择性的整体降解过程，其中隔离膜将一部分细胞质包裹起来，形成称为自噬体的双膜囊泡，并将其内部成分传递至裂解腔室。最近的研究还揭示了选择性降解各种靶标的另一种自噬模式。酵母Atg8及其哺乳动物同源物LC3是泛素样修饰剂，位于隔离膜上，在自噬体的形成中起关键作用。这些蛋白质还参与将特定货物分子选择性掺入自噬体，其中Atg8和LC3分别与Atg19和p62，液泡酶的受体蛋白和疾病相关的蛋白质聚集体相互作用。使用X射线晶体学和NMR，我们在这里报告了Atg8-Atg19和LC3-p62相互作用的结构基础。值得注意的是，Atg8和LC3分别以非常相似的方式相互作用，分别与Atg19和p62相互作用：它们利用保守的疏水口袋识别了Atg19和p62中四氨基酸基序WXXL中的Trp和Leu侧链。在Atg8同源物中。与突变分析一起，我们的结果显示了基本机制，该机制可使Atg8同源物与含WXXL的蛋白质结合，捕获特定的货物分子，从而赋予隔离膜和/或其组装机械以目标选择性。

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