section 20.2
Schematic representation of human LDL receptor showing five domains.
The receptor mediates internalization of LDL and IDL by specific
interaction of their B-100 and E apoprotein moieties with two cysteine-rich
negatively charged areas of domain 1. Domain 2 is homologous to
epidermal growth factor (EGF) precursor, suggesting a possible
evolutionary or functional relationship. [Reproduced with permission from
M. S. Brown and J. L. Goldstein, A receptor-mediated pathway for
cholesterol homeostasis.
S c ie n ce 232,
34 (1986).]
Low-Density Lipoproteins
Distribution and delivery of cholesterol to peripheral tis-
sues are mediated by binding of LDL to specific receptors
on the plasma membrane of target cells. The receptor is a
glycoprotein (whose 5.3-kilobase cDNA has been cloned)
of 839 amino acid residues distributed into five distinct do-
mains (Figure 20-5). Chemical modification of apo B and
apo E, the ligands for the LDL receptor, reveals that pos-
itively charged lysine and arginine residues are essential
for receptor-ligand binding. Binding is probably mediated
by electrostatic interaction between the lysine and argi-
nine residues of apo B and apo E and by the clustered
negatively charged residues of the cysteine-rich region of
the LDL receptor. The gene for the LDL receptor pro-
tein (LRP) is more than 40 kilobases in length. It contains
18 exons, a number of which encode protein sequences ho-
mologous to those in other proteins, namely, a precursor
for epidermal growth factor (EGF), C
component of the
complement, and three clotting and anticlotting proteins
(factor IX and X and protein C).
The number of LDL receptors on the cell membrane
depends on the degree of accumulation of intracellular
cholesterol, which down-regulates the transcription of the
LDL receptor gene. The population of LDL receptors may
be reduced 10-fold by this mechanism. The LDL recep-
tor migrates to areas of the cell membrane specialized for
endocytosis called
coated pit
because of the protein coat
on the cytoplasmic side that consists predominantly of
clathrin (M.W. 180,000).
In vitro,
clathrin spontaneously
self-associates into pentagonal and hexagonal structures.
In vivo,
these structures form a basket-like scaffolding that
mediates invagination of the receptor-rich coated pit. Once
inside the cell, the clathrin dissociates from the endoso-
mal vesicle. ATP-dependent proton pumps in the vesicu-
lar membrane lower the internal pH of these structures,
causing LDL to dissociate from its receptor. The receptor
is recycled to the cell surface. The endosome fuses with
a primary lysosome whose hydrolases (e.g., cathepsins,
acid lipase) degrade LDL to its monomeric constituents
(e.g., amino acids, cholesterol), which are then released
into the cytoplasm (Figure 20-6).
Cholesterol released inside cells is incorporated into an
intracellular pool, which is used for membrane synthe-
sis and for reactions that require a sterol nucleus (e.g.,
formation of steroid hormones or bile acids). Choles-
terol (or its metabolite 26-hydroxycholesterol) suppresses
its own synthesis by inhibiting two sequential enzymes
of mevalonate synthesis—3-hydroxy-3-methylglutamyl
coenzyme A (HMG-CoA) synthase and HMG-CoA reduc-
tase, the rate-limiting enzyme of cholesterol biosynthesis
(Chapter 19). This cholesterol also regulates the number
of receptor sites on the cell membrane and, therefore,
cellular uptake of LDL. Genes for cholesterol synthesis
undergo coordinate induction or repression with regard to
formation of the respective mRNAs (Chapter 19). Some of
the cholesterol is esterified (with oleate and palmitoleate)
into cholesteryl esters by microsomal ACAT, whose ac-
tivity is stimulated by cholesterol. Cholesteryl esters of
LDL contain linoleate, whereas those produced by ACAT
contain predominantly oleate and palmitoleate. In hepa-
tocytes, cholesterol can lead to the increased activity of
cholesterol 7a-hydroxylase, the rate-limiting enzyme in
synthesis of bile acids (Chapter 19).
Thus, the receptor-mediated, LDL-derived cholesterol
meets cellular requirements for cholesterol and prevents
its overaccumulation by inhibiting
de novo
synthesis, suppressing further entry of LDL, and storing
unused cholesterol as cholesteryl esters or exporting it
from the liver as bile acids or other sterol-derived products.
About 75% of high-affinity LDL uptake occurs in the liver.
Despite this elaborate regulatory system, cells can accu-
mulate excessive amounts of cholesteryl esters when the
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