Cited by 809Autophagy in Disease and TherapyUbiquitin and proteasome pathwaysAmyotrophic Lateral Sclerosis Research

Structural Basis for Sorting Mechanism of p62 in Selective Autophagy

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Ichimura, Yoshinobu, Kumanomidou, Taichi, Sou, Yu-shin, Mizushima, Tsunehiro, Ezaki, Junji, Ueno, Takashi, Kominami, Eiki, Yamane, Takashi +2 more·2008·Journal of Biological Chemistry

Abstract

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 1.56 angstroms 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.

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Crossref · 10.1074/jbc.m802182200

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  • SQSTM1 mutations affecting the UBA domain impair ubiquitin recognition, whereas mutations within the LIR domain impact LC3 recognition and substrate delivery to autophagosomes.

    “SQSTM1 mutations affecting the UBA domain impair ubiquitin recognition [130], whereas mutations within the LIR domain impact LC3 recognition and substrate delivery to the autophagosomes [84,131].”

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Authors
Ichimura, Y., Kumanomidou, T., Sou, Y.-S., Mizushima, T., Ezaki, J., Ueno, T., Kominami, E., Yamane, T., Tanaka, K., & Komatsu, M.
Affiliations
  • Juntendo University (JP)
  • Nagoya University (JP)
  • Tokyo Metropolitan Institute of Medical Science (JP)
Corresponding author
Komatsu, Masaaki
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2008-08
Volume
283
Issue
33
Pages
22847-22857
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2125123150
Cited by
803
References
44
Citations by year
2026: 25 · 2025: 35 · 2024: 39 · 2023: 50 · 2022: 36 · 2021: 49 · 2020: 47 · 2019: 55 · 2018: 43 · 2017: 44 · 2016: 55 · 2015: 38 · 2014: 54 · 2013: 49 · 2012: 60
FWCI
31.03
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
p62, selective autophagy, crystal structure, hydrophobic pocket, protein turnover
MeSH terms
Sequestosome-1 Protein, Autophagy, Binding Sites, Carrier Proteins, Lysosomes, Microtubule-Associated Proteins, Recombinant Fusion Proteins, Vacuoles, Sequence Deletion, Adaptor Proteins, Signal Transducing, Maltose-Binding Proteins

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