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The Journal of Lipid Research, Vol. 40, 59-69, January 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity

Correspondence to: M. Rosseneu

A molecular model was built for human lecithin:cholesterol acyltransferase (LCAT) based upon the structural homology between this enzyme and lipases (Peelman et al. 1998. Prot. Sci. 7: 585–597). We proposed that LCAT belongs to the /ß hydrolase fold family, and that the central domain of LCAT consists of a mixed seven-stranded ß-pleated sheet with four -helices and loops linking the ß-strands. The catalytic triad of LCAT was identified as Asp345 and His377, as well as Ser181. This model is used here for the interpretation of the structural defects linked to the point mutations identified in LCAT, which cause either familial LCAT deficiency (FLD) or fish-eye disease (FED).

We show that these mutations occur in separate domains of the 3D structure of the enzyme. Most mutations causing familial LCAT deficiency are either clustered in the vicinity of the catalytic triad or affect conserved structural elements in LCAT. Most mutations causing fish-eye disease are localized on the outer hydrophilic surface of the amphipathic helical segments. These mutations affect only minimally the overall structure of the enzyme, but are likely to impair the interaction of the enzyme with its co-factor and/or substrate.—Peelman, F., J-L. Verschelde, B. Vanloo, C. Ampe, C. Labeur, J. Tavernier, J. Vanderkerckhove, and M. Rosseneu. Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity. J. Lipid Res. 1999. 40: 59–69.

Supplementary key words: lecithin:cholesterol acyltransferase, mutants, enzymatic activity, structure, lipoproteins, reverse cholesterol transport

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