Biogenesis, Structure and Function of Lysosomes
621
LAMP2a and LAMP2b are required for
the operation of two different pathways of
lysosomal proteolysis. A role for the third
splicing isoform, LAMP2c, is not known.
The LAMP2s, like LAMP1 and lysosomal
integral membrane proteins (LIMP)s, are
integral proteins with most of the protein
facing the lysosomal lumen. This portion
of the protein is highly glycosylated, and
this glycosylation protects the proteins
from rapid digestion by the battery of
lysosomal proteases. These glycoproteins
may also protect the inner leaflet of the
lysosomal membrane from digestion by
lumenal lipases.
A recent report of detergent-resistant
lipid raft microdomains in the lysosomal
membrane suggests an additional level of
complexity to lysosomal membrane struc-
ture. The physiological signiFcance of such
microdomains remains to be determined.
Certain
specialized
cells
also
con-
tain lysosome-related organelles that are
thought to be made by pathways similar
to those for lysosomal biogenesis. They
contain not only lysosomal proteins but
also additional proteins. Such lysosome-
related organelles include melanosomes
within melanocytes and retinal pigment
epithelium and lytic granules within cy-
totoxic T-lymphocytes and natural killer
cells. The acrosome of sperm is also a
lysosome-related organelle.
2
Biogenesis of Mammalian Lysosomes
Both lumenal and membrane lysosomal
proteins contain speciFc targeting signals
that are required for their correct localiza-
tion in lysosomes. Receptors or vesicle coat
proteins recognize these targeting signals
and play critical roles in trafFcking the
proteins to lysosomes.
2.1
Proteins in the Lumen
Most lysosomal proteins that are solu-
ble within the lysosomal lumen travel
through the protein secretory pathway.
That is, they are synthesized by polysomes
that are associated with the endoplasmic
reticulum (ER). They typically have a cleav-
able membrane-spanning signal sequence
that is required for their translocation
into the ER lumen. In the ER, the sig-
nal sequence is cleaved, and the resulting
processed protein is glycosylated. The pro-
tein is packaged into coatomer protein
(COP) II-coated vesicles and transferred
to the Golgi where it is recognized by a
phosphotransferase enzyme that transfers
N
-acetyl-glucosamine-1-phosphate to one
or more mannose residues on the lyso-
somal enzyme. A glucosaminidase in the
Golgi removes the glucosamine to gener-
ate the M6P.
The phosphotransferase recognizes the
sugar
group
and
the
features
of
the
polypeptide
to
identify
the
protein
as
belonging to lysosomes. The features of
the protein that are recognized are not
linear but appear to result from protein
folding.
Multiple
lysine
residues
in
a
particular chemical environment and the
distance
from
the
carbohydrate
group
appear to be important determinants of
phosphotransferase recognition (±ig. 1).
Transfer
of
the
lysosomal
protein
through
the
Golgi
may
be
by
COPI-
coated vesicles. Alternatively, the Golgi
may be dynamic with enzyme distribution
determined by forward membrane flow
and retrograde protein retrieval, a process
termed
cisternal maturation
.
All
forms
of
vesicular
transport
re-
quire speciFc
v
esicle membrane
s
oluble
N
-ethylmaleimide
sensitive
a
ttachment
re
ceptor (v-SNARE) and
t
arget membrane
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