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 (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.
Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421.
Yoshinobu
Y
Ichimura
Taichi
T
Kumanomidou
Yu-shin
YS
Sou
Tsunehiro
T
Mizushima
Junji
J
Ezaki
Takashi
T
Ueno
Eiki
E
Kominami
Takashi
T
Yamane
Keiji
K
Tanaka
Masaaki
M
Komatsu
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics; D008247:Lysosomes / Q000502:physiology; D058619:Maltose-Binding Proteins; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D000071456:Sequestosome-1 Protein; D014617:Vacuoles / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D058619:Maltose-Binding Proteins; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D000071456:Sequestosome-1 Protein; C526109:Anxa3 protein, rat; C099718:SQSTM1 protein, human