Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

734 Chapter 13: Intracellular Membrane Traffic
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.
More than 25 distinct receptors are known to participate in receptor-mediated
endocytosis of different types of molecules. They all apparently use clathrin-dependent
internalization routes and are guided into clathrin-coated pits by signals
in their cytoplasmic tails that bind to adaptor proteins in the clathrin coat. Many
of these receptors, like the LDL receptor, enter coated pits irrespective of whether
they have bound their specific ligands. Others enter preferentially when bound
to a specific ligand, suggesting that a ligand-induced conformational change is
required for them to activate the signal sequence that guides them into the pits.
Since most plasma membrane proteins fail to become concentrated in clathrin-coated
pits, the pits serve as molecular filters, preferentially collecting certain
plasma membrane proteins (receptors) over others.
Electron-microscope studies of cultured cells exposed simultaneously to different
labeled ligands demonstrate that many kinds of receptors can cluster in the
same coated pit, whereas some other receptors cluster in different clathrin-coated
pits. The plasma membrane of one clathrin-coated pit can accommodate more
than 100 receptors of assorted varieties.
Specific Proteins Are Retrieved from Early Endosomes and
Returned to the Plasma Membrane
Early endosomes are the main sorting station in the endocytic pathway, just as
the cis and trans Golgi networks serve this function in the secretory pathway. In
the mildly acidic environment of the early endosome, many internalized receptor
proteins change their conformation and release their ligand, as already discussed
for the M6P receptors. Those endocytosed ligands that dissociate from
their receptors in the early endosome are usually doomed to destruction in lysosomes
(although cholesterol is an exception, as just discussed), along with the
other soluble contents of the endosome. Some other endocytosed ligands, however,
remain bound to their receptors, and thereby share the fate of the receptors.
In the early endosome, the LDL receptor dissociates from its ligand, LDL, and
is recycled back to the plasma membrane for reuse, leaving the discharged LDL to
be carried to lysosomes (Figure 13–52). The recycling transport vesicles bud from
long, narrow tubules that extend from the early endosomes. It is likely that the
geometry of these tubules helps the sorting process: because tubules have a large
membrane area enclosing a small volume, membrane proteins become enriched
over soluble proteins. The transport vesicles return the LDL receptor directly to
the plasma membrane.
The transferrin receptor follows a similar recycling pathway as the LDL receptor,
but unlike the LDL receptor it also recycles its ligand. Transferrin is a soluble
LDL
CYTOSOL
RETURN OF LDL RECEPTORS
TO PLASMA MEMBRANE
UNCOATING
FUSION
early
endosome
late
endosome
lysosome
free
cholesterol
endolysosome
hydrolytic
enzymes
Figure 13–52 The receptor-mediated
endocytosis of LDL. Note that the LDL
dissociates from its receptors in the acidic
environment of the early endosome. After
a number of steps, the LDL ends up in
endolysosomes and lysosomes, where it
is degraded to release free cholesterol. In
contrast, the LDL receptors are returned
to the plasma membrane via transport
vesicles that bud off from the tubular
region of the early endosome, as shown.
For simplicity, only one LDL receptor is
shown entering the cell and returning to the
plasma membrane. Whether it is occupied
or not, an LDL receptor typically makes
one round trip into the cell and back to
the plasma membrane every 10 minutes,
making a total of several hundred trips in its
20-hour life-span.