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J. Biol. Chem., Vol. 268, Issue 28, 20747-20755, Oct, 1993
CC Chang, HY Huh, KM Cadigan and TY Chang
Accumulation of cholesterol esters as cytoplasmic lipid droplets within
macrophages and smooth muscle cells is a characteristic feature of early
lesions of atherosclerotic plaque. Intracellularly, an essential element in
forming cholesterol ester from cholesterol is the enzyme acyl-coenzyme
A:cholesterol acyltransferase (ACAT). ACAT is a membrane protein located in
the endoplasmic reticulum. The ACAT protein has never been purified to
homogeneity, and no antibodies directed against ACAT have been reported.
The gene(s) encoding this enzyme had not been isolated. This laboratory had
previously reported the isolation of Chinese hamster ovary cells expressing
human ACAT activity. From DNAs of these cells, we have cloned a 1.2-kb
exonic human genomic DNA. This led to the eventual cloning of a 4-kb cDNA
clone (K1) from a human macrophage cDNA library. Transfection of K1 in
ACAT-deficient mutant Chinese hamster ovary cells complemented the mutant
defect and resulted in the expression of human ACAT activity. K1 contained
an open reading frame of 1650 bp encoding an integral membrane protein of
550 amino acids. Protein homology analysis showed that the predicted K1
protein shared homologous peptide sequences with other enzymes involved in
the catalysis of acyl adenylate formation followed by acyl thioester
formation and acyl transfer. These results indicate that K1 encodes a
structural gene for ACAT. The cDNA reported here should facilitate future
molecular studies on ACAT.
Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells
Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755.
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