Structural basis for sorting mechanism of p62 in selective autophagy
Structural basis for sorting mechanism of p62 in selective autophagy
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DOI：
10.1074/jbc.m802182200
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发表时间：
2008-08-15
影响因子：
4.8
通讯作者：
Komatsu, Masaaki
中科院分区：
文献类型：
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作者：
Ichimura, Yoshinobu;Kumanomidou, Taichi;Komatsu, Masaaki
泛素和LC 3结合蛋白“p62”的自噬降解受损导致细胞质包涵体的形成。然而，关于p62对自噬降解的分选机制知之甚少。在这里，我们确定了一个由11个氨基酸（Ser（334）-Ser（344））组成的小鼠p62的基序，含有保守的酸性和疏水性残基跨物种，作为LC 3识别序列（LRS）。LC 3-LRS复合物在1.56埃分辨率下的晶体结构揭示了p62的Trp（340）和Leu（343）与LC 3的泛素折叠上的不同疏水口袋的相互作用。体内分析表明，缺乏LC 3结合能力的p62突变体在细胞质中积累而不包埋到自噬体中，随后形成如自噬缺陷细胞中的泛素阳性包涵体。这些结果表明，细胞内水平的p62的自噬通过LC 3与p62的直接相互作用被严格调节，并揭示了p62通过自噬的选择性周转控制包涵体的形成。
Impairment of autophagic degradation of the ubiquitin- and LC3-binding protein "p62" leads to the formation of cytoplasmic inclusion bodies. However, little is known about the sorting mechanism of p62 to autophagic degradation. Here we identified a motif of murine p62 consisting of 11 amino acids (Ser(334)-Ser(344)) containing conserved acidic and hydrophobic residues across species, as an LC3 recognition sequence (LRS). The crystal structure of the LC3-LRS complex at 1.56 angstrom resolution revealed interaction of Trp(340) and Leu(343) of p62 with different hydrophobic pockets on the ubiquitin fold of LC3. In vivo analyses demonstrated that p62 mutants lacking LC3 binding ability accumulated without entrapping into autophagosomes in the cytoplasm and subsequently formed ubiquitin- positive inclusion bodies as in autophagy-deficient cells. These results demonstrate that the intracellular level of p62 is tightly regulated by autophagy through the direct interaction of LC3 with p62 and reveal that selective turnover of p62 via autophagy controls inclusion body formation.