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

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 alpha/beta hydrolase fold family, and that the central domain of LCA T consists of a mixed seven-stranded beta-pleated sheet with four alpha-hel ices and loops linking the beta-strands, The catalytic triad of LCAT was id entified as Asp345 and His377, as well as Ser181, This model is used here f or the interpretation of the structural defects linked to the point mutatio ns identified in LCAT which cause either familial LCAT deficiency (FLD) or fish-eye disease (FED). We show that these mutations occur in separate doma ins 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-e ye disease are localized on the outer hydrophilic surface of the amphipathi c helical segments, These mutations affect only minimally the overall struc ture of the enzyme, but are Likely to impair the interaction of the enzyme with its co-factor and/ or substrate.