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A more recent version of this article appeared on February 1, 2006

Papers In Press, published online ahead of print November 10, 2005
J. Lipid Res., doi:10.1194/jlr.M500344-JLR200
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Submitted on August 3, 2005
Revised on October 11, 2005
Accepted on November 10, 2005

Mutation of F417 but not of L418 or L420 in the putative neutral lipid binding domain results in decreased activity of human triacylglycerol hydrolase

Mustafa Alam, Dean Gilham, Dennis E. Vance, and Richard Lehner

Pediatrics and Cell Biology, University of Alberta, Edmonton, Alberta T6G 2S2

Corresponding Author: richard.lehner{at}ualberta.ca

Human triacylglycerol hydrolase (hTGH) has been shown to play a role in hepatic lipid metabolism. TGH hydrolyzes insoluble carboxylic esters at lipid/water interfaces, however, the mechanism by which the enzyme adsorbs to lipid droplets is unclear. Three-dimensional modeling of hTGH predicts that catalytic residues are adjacent to an a-helix that may mediate TGH/lipid interaction. The helix contains a putative neutral lipid-binding domain consisting of an octapeptide FLDLIADV (amino acid residues 417-424) with the consensus sequence FLXLXXXn (where n is a non-polar residue and X is any amino acid except proline) identified in several other proteins that bind or metabolize neutral lipids. Deletion of this a-helix abolished lipolytic activity of hTGH. Replacement of F417 with alanine reduced activity by 40% towards both insoluble and soluble esters, whereas replacement of L418 and L420 with alanine did not. Another potential mechanism of increasing TGH affinity for lipid is via reversible acylation. Molecular modeling predicts C390 is available for covalent acylation. However, neither chemical modification of C390 nor mutation to alanine affected activity. Our findings indicate that F417 but not L418, L420 or C390 participate in substrate hydrolysis by hTGH.


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