622
Biogenesis, Structure and Function of Lysosomes
M6P
Lysine
Lysine
Lysosomal matrix enzyme
Fig. 1
Proposed recognition elements
for the phosphotransferase on a
lysosomal matrix protein. Both mannose
sugars and lysines within a certain
distance from the carbohydrate are
recognized by the phosphotransferase
enzyme. The lysines may also be in a
particular chemical environment created
by neighboring amino acid side chains.
s
oluble
N
-ethylmaleimide sensitive
a
ttach-
ment
re
ceptor (t-SNARE) proteins along
with their regulatory proteins, ADP ri-
bosylation factor (ARF) and ras-related
GTPases (Rabs). The Rabs are especially
important in ensuring speci±city of vesicle
docking. In order for vesicle fusion to oc-
cur, the v-SNARE and t-SNARE ±rst have
to be pried apart. This is accomplished by
N
-ethylmaleimide sensitive factor (NSF), a
protein complex that is an ATPase.
The M6P is recognized by a M6P re-
ceptor (M6PR). There are two types of
M6PR in most cells, and both are inte-
gral membrane proteins associated with
late endosomes, Golgi, and the plasma
membrane. One is 215 kDa and binds
proteins marked with M6P independently
of divalent cations. The other is 46 kDa,
and its binding to lysosomal proteins is
highly dependent on the presence of diva-
lent cations. These different M6PRs may
recognize
different
lysosomal
enzymes
and/or be differentially regulated. In the
trans-Golgi network, M6PR and lysoso-
mal enzymes are packaged into differently
coated vesicles. The M6PR travels to late
endosomes but then recycles to Golgi.
M6PRs thereby avoid entering lysosomes.
A small amount of the M6PRs reside on
the plasma membrane. Any M6P-tagged
proteins that may be secreted instead of
being delivered to lysosomes can bind to
this cell surface M6PR and be delivered
to lysosomes by this route. Interestingly,
the cell surface cation-independent M6PR
also acts as a receptor for insulin-like
growth
factor
II
(IGF-II).
Binding
of
IGF-II to the cation-independent M6PR
may
be
a
mechanism
for
delivery
of
IGF-II to lysosomes. Alternatively, some
aspects of IGF-II growth signaling may
occur
through
the
cation-independent
M6PR.
There are indications that not all lyso-
somal
matrix
proteins
are
targeted
to
lysosomes by M6P. For example, in I-cell
disease, there is a de±ciency of the phos-
photransferase enzyme, so no M6P can
be formed on lysosomal enzymes. As ex-
pected, these cells accumulate degradative
substrates within lysosomes owing to the
de±ciency of lysosomal hydrolases. How-
ever, lysosomes from some cell types from
patients with I-cell disease have almost
normal levels of many lysosomal enzymes.
Such cells must have M6P-independent
lysosomal targeting pathways.
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