620
Biogenesis, Structure and Function of Lysosomes
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ioninskeletal muscle and lymphocytes, where the
ubiquitin-proteasome proteolytic pathway predominates. Lysosomal pathways of
proteolysis operate to some extent in all eukaryotic cells except in mature red blood
cells that do not contain organelles, and there are at least six different pathways by
which proteins can be delivered to lysosomes for digestion.
1
Lysosome Structure
Lysosomes are usually spherical organelles
surrounded by a single membrane. There
are 50 to 1,000 lysosomes per mammalian
cell,
but
a
single
large
or
multilobed
lysosome
called
the
vacuole
in
fungi
and
plants.
Lysosomes
can
be
quite
heterogeneous
in
appearance
and
are
difFcult to identify on the basis of purely
morphological criteria. In fact, spherical
lysosomes in many cell types are able to
fuse into a tubular network.
The
lumen
or
matrix
of
the
lyso-
some contains approximately 50 hydro-
lases most of which are optimally active at
acidic pH. The concentration of some of
these hydrolases is estimated to be in the
range of 100 to 200 mg mL
1
.Thelyso
-
somal lumen also contains a molecular
chaperone of the heat shock protein of 70-
kDa (hsp70) family. The vacuolar lumen of
yeast and plant cells also serves as storage
sites for amino acids, polyphosphates, and
other compounds.
The lysosomal membrane is typically a
single bilayer. It contains phospholipids,
including sphingomyelin, relatively high
concentrations of cholesterol, and lyso-
bisphosphatidic acid. This lipid is also
found in late endosomes and multivesic-
ular bodies. The lysosomal membrane
also
contains
many
different
proteins.
The
v
acuolar proton-pumping ATPase (V-
ATPase) is composed of Fve different
integral
membrane proteins
and
eight
different peripheral membrane proteins.
Some of each class are present in mul-
tiple copies per functional complex. The
V-ATPase subunits are not restricted to
lysosomal membranes since they can also
be
found
in
transport
vesicles,
endo-
somes, Golgi, secretory vesicles, and the
plasma membrane.
Lysosomal membranes also contain sev-
eral transporters. Several different sugar
transporters have been described that can
transport monosaccharides produced in
mammalian lysosomes by digestion of gly-
coconjugates. There is also a polymannose
transporter in the lysosomal membrane
that transfers oligosaccharides from the
cytosol to the lysosome for digestion. Most
amino acids exit lysosomes after prote-
olysis through general or speciFc amino
acid transporters. A cystine transporter,
cystinosin, is an integral lysosomal mem-
brane protein that when mutated leads
to cystinosis.
Lysosome-associated membrane protein
(LAMP) type 2a (LAMP2a) is a receptor for
protein substrates of chaperone-mediated
autophagy (Cma; see Sect. 5.6). LAMP2a
multimerizes in the lysosomal membrane
and
may
form
the
protein
translocon
as well as act as the substrate receptor.
Another isoform of LAMP2 formed by
alternative splicing, LAMP2b, is required
for
docking
or
fusion
of
autophagic
vacuoles and lysosomes, a critical step
in
macroautophagy
(see
Sect. 5.3),
so
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