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 LCAT consists of a mixed seven-stranded beta-pleated sheet with four alpha-helices and loops linking the beta-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
F
Laboratory for Lipoprotein Chemistry, Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, Belgium.
Verschelde
J L
JL
Vanloo
B
B
Ampe
C
C
Labeur
C
C
Tavernier
J
J
Vandekerckhove
J
J
Rosseneu
M
M
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D017124:Conserved Sequence; D006801:Humans; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D007862:Phosphatidylcholine-Sterol O-Acyltransferase