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I. THE LOW DENSITY LIPOPROTEIN PA THWA Y AND NA TURALL Y OCCURRING HYPERCHOLESTEROLEMIA MUTATIONS. The pathway for the receptor-mediated endocytosis of low density lipoprotein (LDL) has been most elegantly and thoroughly characterized by Goldstein, Brown, Anderson, and their collegues (1, 2). LDL, which is a large lipoprotein with a hydrophobic core surrounded by an amphipathic shell (Fig. 1), binds to its receptor (LDL-R) and is carried into the cell by receptor-mediated endocytosis. The internalized lipoprotein is delivered to lysosomes, where cholesterol esters are hydrolysed to liberate cholesterol, and LDL-R is recycled to the plasma membranes (Fig. 2). The liberated cholesterol is used for plasma membranes, bile acids, storage-type cholesterol esters, and steroid hormones. Free cholesterol down-regulates LDL-R synthesis and suppresses expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) "reductase, a key enzyme for cholesterol biosynthesis, by accelerating its degradation. LDL-R-mediated endocytosis of LDL thus limits the cholesterol content in mammalian cells. The LDL-R on the cell surface consists of five domains in a single peptide of 839 amino acids: ligand binding domain (I), domain homologous with the EGF precursor (II), and 0-linked sugar (III), membrane spanning (IV), and cytoplasmic tail (V) domains, in order from the NH2-terminus (Fig. 1). The LDL-R contains approximately 2-4 asparagine-linked (N-linked) sugar chains of the complex type and approximately 18 serine/threonine-linked (0-linked) sugar chains. Most of the 0-linked sugar chains are attached to clusters of serine and threonine in Domain III, and a remaining few 0-linked sugar chains are located in Domain I and/or II. The LDL-R is synthesized in the rough endoplasmic reticulum (ER) as a precursor form of 120,000 daltons that contains endoH-sensitive high-mannose N-linked sugar chains and the core sugars of the 0-linked sugar chains (Fig. 3). The 0-linked sugar chains, N-acetylgalactosamine (GalNAc), are added in the ER or in ER to cis/Golgi. During processing in the Golgi apparatus, the apparent molecular weight increases from 120,000 to 160,000, accompanying conversion of the high mannose N-linked sugar chains to the complex endo H-resistant form, and also elongation of the 0-linked chains by addition of galactose and sialic acid (Fig. 3). Mature LDL-R molecules are then transported from the Golgi to the cell surface. Characterization of mutations in the LDL-R gene is expected to delineate the crucial steps of receptor-mediated endocytosis of LDL. In fact, Goldstein, Brown, and their colleagues have reported that naturally occurring mutations of LDL-R genes apparently induce familial hypercholesterolemia (FH) (1, 2). The FH mutations can be separated into 4 classes: class 1, no receptor synthesized; class 2, recep-

Somatic cell mutants of low density lipoprotein receptor.