Most cholesterol is transported in the blood as cholesteryl esters in the form of lipid–protein particles known as low-density lipoproteins (LDLs) (Figure 13–51). When a cell needs cholesterol for membrane synthesis, it makes transmembrane receptor proteins for LDL and inserts them into its plasma membrane. Once in the plasma membrane, the LDL receptors diffuse until they associate with clathrin-coated pits that are in the process of forming. There, an endocytosis signal in the cytoplasmic tail of the LDL receptors binds the membrane-bound adaptor protein AP2 after its conformation has been locally unlocked by binding to PI(4,5)P2 on the plasma membrane. Coincidence detection, as discussed earlier, thus imparts both efficiency and selectivity to the process (see Figure 13–9). AP2 then recruits clathrin to initiate endocytosis.
Since coated pits constantly pinch off to form coated vesicles, any LDL particles bound to LDL receptors in the coated pits are rapidly internalized in coated vesicles. After shedding their clathrin coats, the vesicles deliver their contents to early endosomes. Once the LDL and LDL receptors encounter the low pH in early endosomes, LDL is released from its receptor and is delivered via late endosomes to lysosomes. There, the cholesteryl esters in the LDL particles are hydrolyzed to free cholesterol, which is now available to the cell for new membrane synthesis (Movie 13.3). If too much free cholesterol accumulates in a cell, the cell shuts off both its own cholesterol synthesis and the synthesis of LDL receptors, so that it ceases both to make or to take up cholesterol.
This regulated pathway for cholesterol uptake is disrupted in individuals who inherit defective genes encoding LDL receptors. The resulting high levels of blood cholesterol predispose these individuals to develop atherosclerosis prematurely, and many would die at an early age of heart attacks resulting from coronary artery disease if they were not treated with drugs such as statins that lower the level of blood cholesterol. In some cases, the receptor is lacking altogether. In others, the receptors are defective—in either the extracellular binding site for LDL or the
Figure 13–50 Schematic representation of macropinocytosis. cell signaling events lead to a reprogramming of actin dynamics, which in turn triggers the formation of cell-surface ruffles. as the ruffles collapse back onto the cell surface, they nonspecifically trap extracellular fluid and macromolecules and particles contained in it, forming large vacuoles, or macropinosomes, as shown.
Figure 13–51 A low-density lipoprotein (LDL) particle. each spherical particle has a mass of 3 × 106 daltons. It contains a core of about 1500 cholesterol molecules esterified to long-chain fatty acids. a lipid monolayer composed of about 800 phospholipid and 500 unesterified cholesterol molecules surrounds the core of cholesteryl esters. a single molecule of apolipoprotein b, a 500,000-dalton beltlike protein, organizes the particle and mediates the specific binding of ldl to cell-surface ldl receptors.
intracellular binding site that attaches the receptor AP2 adaptor protein in clathrin-coated pits. In the latter case, normal numbers of LDL receptors are present, but they fail to become localized in clathrin-coated pits. Although LDL binds to the surface of these mutant cells, it is not internalized, directly demonstrating the importance of clathrin-coated pits for the receptor-mediated endocytosis of cholesterol.