Receptor-Mediated Regulation of Cholesterol Metabolism
Cholesterol homeostasis is dependent on the action of specific lipoprotein receptors on various cells (especially within the liver) that mediate lipoprotein uptake and degradation. There are at least two distinct hepatic lipoprotein receptors: the apo-B,E(LDL) receptor and the apo-E receptor, which is postulated to be the chylomicron remnant receptor. They are independently regulated and display unique ligand specificity. In addition, the apo-B,E(LDL) and the apo-E receptors differ in apparent molecular weight (130,000 and 56,000, respectively). However, both receptors possess a region within their amino acid sequence that is enriched in acidic amino acids (glutamate and aspartate) and that is postulated to be the ligand-binding domain. The tentative identification of acidic amino acids within the receptors as being essential in mediating ligand interactions is based primarily on data showing that basic amino acids (lysine and arginine) of the ligands (apo E and apo B) mediate receptor binding. The receptor-binding domain of apo E has been localized to basic amino acids in the vicinity of residues 140 to 160. Naturally occurring variants of apo E with single amino acid substitutions in this region of the molecule are defective in their abilities to bind to the lipoprotein receptors and predispose affected individuals to develop type III hyperlipoproteinemia. Recently, it has been possible to define more clearly essential residues within this region of the apo E molecule by using site-specific mutagenesis. A natural extension of the studies defining the receptor-binding domain of apo E has been the identification of two basic regions of apo B that appear to mediate the interaction of this apolipoprotein with lipoprotein receptors. Eventually, it will be possible to develop a model describing ligand-receptor interactions; presumably, these occur through the interaction of key acidic amino acids of the receptors with the key basic amino acids of apo B and apo E.
KeywordsBasic Amino Acid Cholesterol Metabolism Lipoprotein Receptor Acidic Amino Acid Single Amino Acid Substitution
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