The Low-Density Lipoprotein Receptor
The low-density lipoprotein (LDL) receptor is a prototype for a class of cell surface receptors that bind lipoproteins and other circulating macromolecules and carry them into cells by receptor-mediated endocytosis. The human LDL receptor is a single-chain transmembrane glycoprotein of 839 amino acids. It specifically binds lipoproteins that contain apo B-100 and the active form of apo E. The ligand-binding domain comprises the 292 amino-terminal amino acids and is composed of a cysteine-rich sequence of 40 amino acids that is repeated seven times with minor variations. The cytoplasmic domain, composed of 50 amino acids at the carboxyl-terminal end of the protein, serves to direct the receptor to coated pits, where the bound LDL is rapidly internalized. Between these two ends of the protein there is a 400-amino-acid region that is homologous to the precursor for epidermal growth factor, a 58-amino-acid region that contains up to 18 carbohydrate chains linked to serine or threonine, and a 22-amino-acid membrane-spanning region.
Mutations in the LDL receptor gene are responsible for familial hypercholesterolemia (FH), an autosomal dominant disease that affects one out of every 500 persons. Individuals with a single mutant gene express half the normal number of LDL receptors and have plasma LDL levels that are approximately twofold above normal. Individuals with two mutant LDL receptor genes have the clinical syndrome of homozygous familial hypercholesterolemia. They have five-to eightfold elevations in plasma LDL and usually develop myocardial infarctions in childhood.
The molecular defects in 12 patients with familial hypercholesterolemia have been elucidated through cloning and sequencing of the relevant portions of the mutant LDL receptor genes. Study of these mutations has revealed the functions of various domains in the receptor protein. These studies have also revealed features of the protein that are required for normal transport to the cell surface.
The LDL receptor deficiency states can be treated through use of drugs that stimulate the production of new LDL receptors or by means of liver transplantation, which provides a source of LDL receptors in FH homozygotes.
KeywordsBile Acid Familial Hypercholesterolemia Familial Hypercholesterolemia Heterozygous Familial Hypercholesterolemia Ovarian Corpus Luteum
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