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J. Biol. Chem., Vol. 283, Issue 32, 21847-21852, August 8, 2008

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Physiological pH and Acidic Phospholipids Contribute to Substrate Specificity in Lipidation of Atg8^*

Kyoko Oh-oka, Hitoshi Nakatogawa^¶, and Yoshinori Ohsumi¹

From the Department of Cell Biology, National Institute for Basic Biology, and the Department of Basic Biology, Graduate University for Advanced Studies, Okazaki 444-8585, Japan and ^¶PRESTO, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Yeast Atg8 and its mammalian homolog LC3 are ubiquitin-like proteins involved in autophagy, a primary pathway for degradation of cytosolic constituents in vacuoles/lysosomes. Whereas the lipid phosphatidylethanolamine (PE) was identified as the sole in vivo target of their conjugation reactions, in vitro studies showed that the same system can mediate the conjugation of these proteins with phosphatidylserine as efficiently as with PE. Here, we show that, in contrast to PE conjugation, the in vitro phosphatidylserine conjugation of Atg8 is markedly suppressed at physiological pH. Furthermore, the addition of acidic phospholipids to liposomes also results in the preferential formation of the Atg8-PE conjugate. We have successfully captured authentic thioester intermediates, allowing us to elucidate which step in the conjugation reaction is affected by these changes in pH and membrane lipid composition. We propose that these factors contribute to the selective formation of Atg8-PE in the cell.

Received for publication, March 6, 2008 , and in revised form, June 3, 2008.

^* This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed. Tel.: 81-564-55-7515; Fax: 81-564-55-7516; E-mail: yohsumi{at}nibb.ac.jp.

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