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J. Biol. Chem., Vol. 281, Issue 52, 40273-40282, December 29, 2006

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Membrane Topology and Identification of Key Functional Amino Acid Residues of Murine Acyl-CoA:Diacylglycerol Acyltransferase-2^*

Scot J. Stone¹, Malin C. Levin, and Robert V. Farese, Jr.^¶||

From the Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158 and the Cardiovascular Research Institute, the ^¶Departments of Medicine and of Biochemistry & Biophysics, and the ^||Diabetes Center, University of California, San Francisco, California 94143

Triacylglycerols are the predominant molecules of energy storage in eukaryotes. However, excessive accumulation of triacylglycerols in adipose tissue leads to obesity and, in nonadipose tissues, is associated with tissue dysfunction. Hence, it is of great importance to have a better understanding of the molecular mechanisms of triacylglycerol synthesis. The final step in triacylglycerol synthesis is catalyzed by the acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2. Although recent studies have shed light on metabolic functions of these enzymes, little is known about the molecular aspects of their structures or functions. Here we report the topology for murine DGAT2 and the identification of key amino acids that likely contribute to enzymatic function. Our data indicate that DGAT2 is an integral membrane protein with both the N and C termini oriented toward the cytosol. A long hydrophobic region spanning amino acids 66-115 likely comprises two transmembrane domains or, alternatively, a single domain that is embedded in the membrane bilayer. The bulk of the protein lies distal to the transmembrane domains. This region shares the highest degree of homology with other enzymes of the DGAT2 family and contains a sequence HPHG that is conserved in all family members. Mutagenesis of this sequence in DGAT2 demonstrated that it is required for full enzymatic function. Additionally, a neutral lipid-binding domain that is located in the putative first transmembrane domain was also required for full enzymatic function. Our findings provide the first insights into the topography and molecular aspects of DGAT2 and related enzymes.

Received for publication, August 21, 2006 , and in revised form, October 2, 2006.

^* This work was supported by an American Heart Association Scientist Development grant (to S. J. S.), a Hillblom postdoctoral fellowship (to M. C. L.), National Institutes of Health Grant 5R01-DK065599 (to R. V. F.), and the J. David Gladstone Institutes. 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: The Gladstone Institute of Cardiovascular Disease, 1650 Owens St., San Francisco, CA 94158. Tel.: 415-734-2000; Fax: 415-355-0960; E-mail: sstone{at}gladstone.ucsf.edu.

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