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J. Biol. Chem., Vol. 283, Issue 25, 17211-17220, June 20, 2008

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The C-terminal Region of Human Adipose Triglyceride Lipase Affects Enzyme Activity and Lipid Droplet Binding^*

Martina Schweiger¹, Gabriele Schoiswohl¹, Achim Lass, Franz P. W. Radner, Guenter Haemmerle, Roland Malli, Wolfgang Graier, Irina Cornaciu, Monika Oberer, Robert Salvayre^¶, Judith Fischer^||, Rudolf Zechner, and Robert Zimmermann²

From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria, the Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria, the ^¶INSERM, U-466, University Paul Sabatier, Institute Fédératif de Recherche-31, CHU Rangueil, 31432 Toulouse, France, and the ^||Centre National de Génotypage, 91057 Evry Cedex, France

Adipose triglyceride lipase (ATGL) catalyzes the first step in the hydrolysis of triacylglycerol (TG) generating diacylglycerol and free fatty acids. The enzyme requires the activator protein CGI-58 (or ABHD5) for full enzymatic activity. Defective ATGL function causes a recessively inherited disorder named neutral lipid storage disease that is characterized by systemic TG accumulation and myopathy. In this study, we investigated the functional defects associated with mutations in the ATGL gene that cause neutral lipid storage disease. We show that these mutations lead to the expression of either inactive enzymes localizing to lipid droplets (LDs) or enzymatically active lipases with defective LD binding. Additionally, our studies assign important regulatory functions to the C-terminal part of ATGL. Truncated mutant ATGL variants lacking 220 amino acids of the C-terminal protein region do not localize to LDs. Interestingly, however, these mutants exhibit substantially increased TG hydrolase activity in vitro (up to 20-fold) compared with the wild-type enzyme, indicating that the C-terminal region suppresses enzyme activity. Protein-protein interaction studies revealed an increased binding of truncated ATGL to CGI-58, suggesting that the C-terminal part interferes with CGI-58 interaction and enzyme activation. Compared with the human enzyme, the C-terminal region of mouse ATGL is much less effective in suppressing enzyme activity, implicating species-dependent differences in enzyme regulation. Together, our results demonstrate that the C-terminal region of ATGL is essential for proper localization of the enzyme and suppresses enzyme activity.

Received for publication, December 28, 2007 , and in revised form, April 29, 2008.

^* This work was supported by Grant P18434 [GenBank] -B05 from the Austrian Fonds zur Förderung der wissenschaftlichen Forschung and "GOLD - Genomics of Lipid-Associated Disorders," which is part of the Austrian Genome Project "GEN-AU Genome Research in Austria" and is funded by the Austrian Ministry for Education, Research, and Culture. 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: Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31A, A-8010 Graz, Austria. Tel.: 43-316-3801900; E-mail: robert.zimmermann{at}uni-graz.at.

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