Structural Basis for Sorting Mechanism of p62 in Selective Autophagy

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 (S...

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Published in:The Journal of biological chemistry 2008-08, Vol.283 (33), p.22847-22857
Main Authors: Ichimura, Yoshinobu, Kumanomidou, Taichi, Sou, Yu-shin, Mizushima, Tsunehiro, Ezaki, Junji, Ueno, Takashi, Kominami, Eiki, Yamane, Takashi, Tanaka, Keiji, Komatsu, Masaaki
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - physiology
Autophagy - physiology
Binding Sites
Carrier Proteins - chemistry
Carrier Proteins - genetics
Lysosomes - physiology
Maltose-Binding Proteins
Microtubule-Associated Proteins - chemistry
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - physiology
Recombinant Fusion Proteins - chemistry
Recombinant Fusion Proteins - metabolism
Sequence Deletion
Sequestosome-1 Protein
Vacuoles - physiology
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Summary: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 (Ser334-Ser344) containing conserved acidic and hydrophobic residues across species, as an LC3 recognition sequence (LRS). The crystal structure of the LC3-LRS complex at 1.56Å resolution revealed interaction of Trp340 and Leu343 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M802182200