The LDL Receptor — Structural Insights

Abstract

Low density lipoprotein (LDL), the major cholesterol-carrying class of lipopro-teins in human plasma, is taken up by hepatic and extrahepatic cells via receptor-mediated endocytosis. In this process, LDL particles bind to cell-surface receptors, the LDL receptors, which are localized in specialized regions of the plasma membrane called coated pits. Coated pits make up 2% of the surface area of a normal human fibroblast and are characteristic indentations displaying an electron-dense coat on their cytoplasmic side consisting mainly of a Polypeptide called clathrin. After LDL has bound to LDL receptors, it is rapidly taken up into the cell through invagination and pinching-off of the coated pits to form coated vesicles containing the receptor-LDL complex. Along its intracellular route, in the endosome compartment, the complex dissociates; LDL is delivered to lysosomes where the particles are degraded, and unoccupied LDL receptors recycle back to the cell surface, ready to bind and internalize new LDL particles. Normal functions of the LDL receptor pathway is of great importance for cellular cholesterol homeostasis; the LDL-derived cholesterol exerts feedback-control on the level of the enzyme catalyzing the rate-limiting step in cellular cholesterol synthesis, 3-hydroxymethyl-glutaryl-CoA reductase, as well as on the number of LDL receptors, thereby protecting the cell from overaccumulation of cholesterol. In addition, the cholesterol derived from LDL is rapidly converted to cholesterylesters for storage in droplets via stimulation of acyl-CoA: cholesterol acyltransferase.