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J. Biol. Chem., Vol. 283, Issue 33, 22847-22857, August 15, 2008

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Structural Basis for Sorting Mechanism of p62 in Selective Autophagy^*

Yoshinobu Ichimura¹, Taichi Kumanomidou¹, Yu-shin Sou^¶1, Tsunehiro Mizushima, Junji Ezaki, Takashi Ueno, Eiki Kominami, Takashi Yamane, Keiji Tanaka^¶, and Masaaki Komatsu^¶||2

From the Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, the Department of Biotechnology, Graduate School of Engineering, Nagoya University, Chikusa-ku, Nagoya 464-8603, the ^¶Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, and ^||PRESTO, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan

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.

Received for publication, March 19, 2008 , and in revised form, May 19, 2008.

The atomic coordinates and structure factors (code 2ZJD) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by grants from the Japan Science and Technology Agency (to M. K.), the Ministry of Education, Science and Culture of Japan (to M. K. and K. T.), the Target Protein Project of Ministry of Education, Science and Culture of Japan (to T. M. and K. T.), and Takeda Science Foundation (to K. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 81-3-3823-2105; Fax: 81-3-3823-2237; E-mail: mkomatsu{at}rinshoken.or.jp.

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