leading to its premature degradation (Chapter 16); still other mutations reduce the ability of the LDL receptor to bind LDL tightly. A particularly informative group of mutant receptors are expressed on the cell surface and bind LDL normally but cannot mediate the internalization of bound LDL. Analyses of such defective LDL receptors led to the concept of internalization sequences in cell-surface proteins destined for endocytosis by means of clathrin-coated pits. As discussed in Chapter 17, such sorting signals, located in the cy-tosolic domains of certain membrane proteins, play a key role in directing these proteins to particular vesicles.

The results of these pioneering studies and other research led to the current model for the receptor-mediated endocy-

tosis of LDL and other receptor-ligand combinations detailed in Chapter 17 (see in particular Figure 17-28) and summarized in Figure 18-10b. After internalized LDL particles reach lysosomes, lysosomal proteases hydrolyze their surface apolipoproteins and lysosomal cholesteryl esterases hydrolyze their core cholesteryl esters. The unesterified cholesterol is then free to leave the lysosome and be used as necessary by the cell in the synthesis of membranes or various cholesterol derivatives. The export of cholesterol from lyso-somes depends on the NPC1 protein mentioned previously.

If LDLR-mediated endocytosis were not regulated, cells would continuously take up LDL and accumulate massive amounts of LDL-derived cholesterol because of the recycling

▲ EXPERIMENTAL FIGURE 18-15 Pulse-chase experiment demonstrates precursor-product relations in cellular uptake of LDL. Cultured normal human skin fibroblasts were incubated in a medium containing 125I-LDL for 2 hours at 4 °C (the pulse). After excess 125I-LDL not bound to the cells was washed away, the cells were incubated at 37 °C for the indicated amounts of time in the absence of external LDL (the chase). The amounts of surface-bound, internalized, and degraded (hydrolyzed) 125I-LDL were measured as in the experiments presented in Figure 18-14. Binding but not internalization or hydrolysis of LDL apoB-100 occurs during the 4 °C pulse. The data show the very rapid disappearance of bound 125I-LDL from the surface as it is internalized after the cells have been warmed to allow membrane movements. After a lag period of 15-20 minutes, lysosomal degradation of the internalized 125I-LDL commences. [See M. S. Brown and J. L. Goldstein, 1976, Cell 9:663.]

▲ FIGURE 18-16 Model for the selective uptake of cholesteryl esters from HDL mediated by the receptor SR-BI.

After HDL binding to SR-BI 1, cholesteryl esters In the core are selectively transferred to a cell's membrane 2 and then Into the cytosol 3 by as-yet-unknown mechanisms. The remaining lipid-

of receptors and the large reservoir of LDL in the bloodstream. However, an elegant regulatory system described in Section 18.4 limits LDL uptake. LDL delivers most of its cholesterol to the liver, which expresses the majority of the body's LDL receptors. The LDL receptor not only interacts with apoB-100 on the surfaces of LDL particles, but also binds to apoE on the surfaces of chylomicron remnants and intermediate-density lipoprotein (IDL) particles. A related receptor called LRP (LDLR-related protein) recognizes apoE but not apoB-100; thus LRP mediates the endocytosis of chylomicron remnants and IDL, but not LDL, by hepato-cytes and some other cells (see Figure 18-13b).

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