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J. Biol. Chem., Vol. 282, Issue 11, 8036-8043, March 16, 2007

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The Crystal Structure of Atg3, an Autophagy-related Ubiquitin Carrier Protein (E2) Enzyme that Mediates Atg8 Lipidation^*

Yuya Yamada, Nobuo N. Suzuki, Takao Hanada, Yoshinobu Ichimura, Hiroyuki Kumeta, Yuko Fujioka, Yoshinori Ohsumi, and Fuyuhiko Inagaki¹

From the Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, N-12, W-6, Kita-ku, Sapporo 060-0812, Japan and Division of Molecular Cell Biology, National Institute for Basic Biology, 38 Nishigonaka, Myodaiji, Okazaki 444-8585, Japan

Atg3 is an E2-like enzyme that catalyzes the conjugation of Atg8 and phosphatidylethanolamine (PE). The Atg8-PE conjugate is essential for autophagy, which is the bulk degradation process of cytoplasmic components by the vacuolar/lysosomal system. We report here the crystal structure of Saccharomyces cerevisiae Atg3 at 2.5-Å resolution. Atg3 has an /-fold, and its core region is topologically similar to canonical E2 enzymes. Atg3 has two regions inserted in the core region, one of which consists of 80 residues and has a random coil structure in solution and another with a long -helical structure that protrudes from the core region as far as 30Å_. In vivo and in vitro analyses suggested that the former region is responsible for binding Atg7, an E1-like enzyme, and that the latter is responsible for binding Atg8. A sulfate ion was bound near the catalytic cysteine of Atg3, suggesting a possible binding site for the phosphate moiety of PE. The structure of Atg3 provides a molecular basis for understanding the unique lipidation reaction that Atg3 carries out.

Received for publication, December 14, 2006 , and in revised form, January 16, 2007.

The atomic coordinates and structure factors (code 2DYT) 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 in part by Grant-in-aids for Young Scientists (B) 17790048 and for scientific research on priority areas as well as by the National Project on Protein Structural and Functional Analyses from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. This work was carried out under the National Institute for Basic Biology (NIBB) Cooperative Research Program (4–148). 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 To whom correspondence should be addressed. Tel.: 81-11-706-3975; Fax: 81-11-706-4979; E-mail: finagaki{at}pharm.hokudai.ac.jp.

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