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Journal of Lipid Research, Vol. 47, 1803-1811, August 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Substrate specificity of lipoprotein lipase and endothelial lipase: studies of lid chimeras

Nathalie Griffon^1,*, Elaine C. Budreck^*, Christopher J. Long^*, Uli C. Broedl^*, Dawn H. L. Marchadier^*, Jane M. Glick and Daniel J. Rader^*

^* Department of Medicine and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Published, JLR Papers in Press, May 10, 2006.

¹ To whom correspondence should be addressed. e-mail: griffon{at}mail.med.upenn.edu

The triglyceride (TG) lipase gene subfamily, consisting of LPL, HL, and endothelial lipase (EL), plays a central role in plasma lipoprotein metabolism. Compared with LPL and HL, EL is relatively more active as a phospholipase than as a TG lipase. The amino acid loop or "lid" covering the catalytic site has been implicated as the basis for the difference in substrate specificity between HL and LPL. To determine the role of the lid in the substrate specificity of EL, we studied EL in comparison with LPL by mutating specific residues of the EL lid and exchanging their lids. Mutation studies showed that amphipathic properties of the lid contribute to substrate specificity. Exchanging lids between LPL and EL only partially shifted the substrate specificity of the enzymes. Studies of a double chimera possessing both the lid and the C-terminal domain (C-domain) of EL in the LPL backbone showed that the role of the lid in determining substrate specificity does not depend on the nature of the C-domain of the lipase. Using a kinetic assay, we showed an additive effect of the EL lid on the apparent affinity for HDL₃ in the presence of the EL C-domain.

Abbreviations: appK_m, apparent affinity of the enzyme for the phospholipid present in HDL₃ as substrate; C-domain, C-terminal domain; EL, endothelial lipase; PL, phospholipid; TG, triglyceride; TG/PL ratio, ratio of triglyceride lipase activity to phospholipase activity

Supplementary key words hepatic lipase • triglyceride • phospholipid

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