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 α/β hydrolase fold family, and that the central domain of LCAT consi...
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| Format: | Article |
| Language: | English |
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Elsevier
1999-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520333393 |
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| author | F. Peelman J-L. Verschelde B. Vanloo C. Ampe C. Labeur J. Tavernier J. Vandekerckhove M. Rosseneu |
| author_facet | F. Peelman J-L. Verschelde B. Vanloo C. Ampe C. Labeur J. Tavernier J. Vandekerckhove M. Rosseneu |
| author_sort | F. Peelman |
| collection | DOAJ |
| description | 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 α/β hydrolase fold family, and that the central domain of LCAT consists of a mixed seven-stranded β-pleated sheet with four α-helices and loops linking the β-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. |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T01:01:24Z |
| publishDate | 1999-01-01 |
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| series | Journal of Lipid Research |
| spelling | doaj.art-23a18c9a6c4c44ae858b7873a35ae2492022-12-21T22:09:25ZengElsevierJournal of Lipid Research0022-22751999-01-014015969Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activityF. Peelman0J-L. Verschelde1B. Vanloo2C. Ampe3C. Labeur4J. Tavernier5J. Vandekerckhove6M. Rosseneu7Laboratory for Lipoprotein Chemistry Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumFlanders Interuniversity Institute for Biotechnology, Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumLaboratory for Lipoprotein Chemistry Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumFlanders Interuniversity Institute for Biotechnology, Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumLaboratory for Lipoprotein Chemistry Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumFlanders Interuniversity Institute for Biotechnology, Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumFlanders Interuniversity Institute for Biotechnology, Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumTo whom correspondence should be addressed.; Laboratory for Lipoprotein Chemistry Department of Biochemistry, Faculty of Medicine, Universiteit Gent, B-9000 Gent, BelgiumA 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 α/β hydrolase fold family, and that the central domain of LCAT consists of a mixed seven-stranded β-pleated sheet with four α-helices and loops linking the β-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.http://www.sciencedirect.com/science/article/pii/S0022227520333393lecithin:cholesterol acyltransferasemutantsenzymatic activitystructurelipoproteinsreverse cholesterol transport |
| spellingShingle | F. Peelman J-L. Verschelde B. Vanloo C. Ampe C. Labeur J. Tavernier J. Vandekerckhove M. Rosseneu Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity Journal of Lipid Research lecithin:cholesterol acyltransferase mutants enzymatic activity structure lipoproteins reverse cholesterol transport |
| title | Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity |
| title_full | Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity |
| title_fullStr | Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity |
| title_full_unstemmed | Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity |
| title_short | Effects of natural mutations in lecithin:cholesterol acyltransferase on the enzyme structure and activity |
| title_sort | effects of natural mutations in lecithin cholesterol acyltransferase on the enzyme structure and activity |
| topic | lecithin:cholesterol acyltransferase mutants enzymatic activity structure lipoproteins reverse cholesterol transport |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520333393 |
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