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J. Biol. Chem., Vol. 278, Issue 39, 37083-37091, September 26, 2003

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Human Homologues of LAG1 Reconstitute Acyl-CoA-dependent Ceramide Synthesis in Yeast^*

Isabelle Guillas , James C. Jiang , Christine Vionnet , Carole Roubaty , Danièle Uldry , Rachel Chuard , Jinqing Wang , S. Michal Jazwinski  and Andreas Conzelmann  ¶

From the Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland and the Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

Lag1p and Lac1p are two highly homologous membrane proteins of the endoplasmic reticulum. lag1 lac1 double mutants in Saccharomyces cerevisiae lack an acyl-CoA-dependent ceramide synthase and are either very sick or nonviable, depending on the genetic background. LAG1 and LAC1 are members of a large eukaryotic gene family that shares the Lag1 motif, and some members of this family additionally contain a DNA-binding HOX homeodomain. Here we show that several human LAG1 homologues can rescue the viability of lag1 lac1 yeast cells and restore acyl-CoA-dependent ceramide and sphingolipid biosynthesis. When tested in a microsomal assay, Lac1p and Lag1p had a strong preference for C26:0-CoA over C24:0-CoA, C20-CoA, and C16-CoA, whereas some human homologues preferred C24:0-CoA and CoA derivatives with shorter fatty acids. This suggests that LAG1 proteins are related to substrate recognition and to the catalytic activity of ceramide synthase enzymes. CLN8, another human LAG1 homologue implicated in ceroid lipofuscinosis, could not restore viability to lag1 lac1 yeast mutants.

Received for publication, July 14, 2003

^* This work was supported by grants from the NIA, National Institutes of Health (to S. M. J.) and by Grant 31-67188.01 from the Swiss National Science Foundation (to A. C.). 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.

^¶ To whom correspondence should be addressed: Division of Biochemistry, Dept. of Medicine, University of Fribourg, Rte. du Musée 5, CH-1700 Fribourg, Switzerland. Tel.: 41-26-300-8630; Fax: 41-26-300-9735; E-mail: andreas.conzelmann{at}unifr.ch.

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