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

728 Chapter 13: Intracellular Membrane Traffic
lysosomal hydrolase
precursor
mannose
M6P receptor
from ER
TRANSPORT TO
ENDOSOME
ATP ADP + P i
ADDITION OF
P-GlcNAc
UNCOVERING OF
M6P SIGNAL
BINDING TO
M6P RECEPTOR
clathrin coat
transport
vesicle
retromer
coat
H +
DISSOCIATION
AT ACIDIC pH
REMOVAL OF
PHOSPHATE
lysosomal
hydrolase
precursor
RECEPTOR RETRIEVAL
M6P receptor in
budding vesicle
early endosome
cis
Golgi
network
trans
Golgi
network
Golgi apparatus
adding the M6P units to oligosaccharides must reside somewhere in the polypeptide
chain of each hydrolase. Genetic engineering experiments have revealed that
the recognition signal is a cluster of neighboring amino acids on each protein’s
surface, known as a signal patch (Figure 13–46). Since most lysosomal hydrolases
contain multiple oligosaccharides, they acquire many M6P groups, providing a
high-affinity signal for the M6P receptor.
MBoC6 m13.44/13.46
Defects in the GlcNAc Phosphotransferase Cause a Lysosomal
Storage Disease in Humans
Genetic defects that affect one or more of the lysosomal hydrolases cause a number
of human lysosomal storage diseases. The defects result in an accumulation
of undigested substrates in lysosomes, with severe pathological consequences,
most often in the nervous system. In most cases, there is a mutation in a structural
gene that codes for an individual lysosomal hydrolase. This occurs in Hurler’s
disease, for example, in which the enzyme required for the breakdown of certain
types of glycosaminoglycan chains is defective or missing. The most severe form
of lysosomal storage disease, however, is a very rare inherited metabolic disorder
called inclusion-cell disease (I-cell disease). In this condition, almost all of the
hydrolytic enzymes are missing from the lysosomes of many cell types, and their
undigested substrates accumulate in these lysosomes, which consequently form
large inclusions in the cells. The consequent pathology is complex, affecting all
organ systems, skeletal integrity, and mental development; individuals rarely live
beyond six or seven years.
I-cell disease is due to a single gene defect and, like most genetic enzyme deficiencies,
it is recessive—that is, it occurs only in individuals having two copies
of the defective gene. In patients with I-cell disease, all the hydrolases missing
from lysosomes are found in the blood: because they fail to sort properly in the
Golgi apparatus, they are secreted rather than transported to lysosomes. The
mis-sorting has been traced to a defective or missing GlcNAc phosphotransferase.
Because lysosomal enzymes are not phosphorylated in the cis Golgi network,
the M6P receptors do not segregate them into the appropriate transport vesicles
in the TGN. Instead, the lysosomal hydrolases are carried to the cell surface and
secreted.
In I-cell disease, the lysosomes in some cell types, such as hepatocytes, contain
a normal complement of lysosomal enzymes, implying that there is another
Figure 13–45 The transport of newly
synthesized lysosomal hydrolases to
endosomes. The sequential action of two
enzymes in the cis and trans Golgi network
adds mannose 6-phosphate (M6P) groups
to the precursors of lysosomal enzymes
(see Figure 13–46). The M6P-tagged
hydrolases then segregate from all other
types of proteins in the TGN because
adaptor proteins (not shown) in the clathrin
coat bind the M6P receptors, which, in
turn, bind the M6P-modified lysosomal
hydrolases. The clathrin-coated vesicles
bud off from the TGN, shed their coat,
and fuse with early endosomes. At the
lower pH of the endosome, the hydrolases
dissociate from the M6P receptors, and the
empty receptors are retrieved in retromercoated
vesicles to the TGN for further
rounds of transport. In the endosomes,
the phosphate is removed from the M6P
attached to the hydrolases, which may
further ensure that the hydrolases do not
return to the TGN with the receptor.