Biogenesis, Structure and Function of Lysosomes
623
2.2
Proteins in the Membrane
Lysosomal membrane proteins are also
made from polysomes associated with the
ER. They insert into the ER membrane
because of a hydrophobic stretch of 22
to 26 amino acids within the protein
sequence. These proteins contain critical
amino acids in their cytosolic regions
that direct their targeting to lysosomes
(Fig. 2). The sequences are remarkably
simple and consist of a tyrosine and a
bulky hydrophobic amino acid that are
present within the last four amino acids
of the carboxy terminus. Alternatively, a
leucine, typically in the form of a dileucine
motif, can also target membrane proteins
to lysosomes.
Heterotetrameric adaptor protein (AP)
complexes, AP-1, AP-2, AP-3, and AP-4,
will all bind tyrosine- or dileucine-based
motifs. AP-1 is responsible for recycling of
the M6PRs from endosomes to the Golgi.
AP-2 is involved in clathrin-mediated in-
ternalization from the plasma membrane
and is important for the internalization
of secreted lysosomal enzymes. AP-3 is
important for the intracellular biogene-
sis of lysosomes. AP-4 is localized to the
Golgi and may also be involved in lyso-
some biogenesis.
LAMP2
LAMP1
LIMP1
GLKRHHTGYEQF c
GIRKRSHAGYQTI c
KKSIRSGYEVM c
GSTDEGTADERAPLIRT c
n
n
n
n
LIMP2
Lumen
Lysosomal membrane
Cytosol
=
Sugars
Fig. 2
Diagrammatic structures of integral lysosomal membrane proteins. n
=
amino
terminus; c
=
carboxyl terminus. LAMPs and LIMPs are deFned in the text. The amino acid
sequences of the cytosolic tails are shown. Amino acids experimentally shown to be
important in targeting the protein to the lysosomal membrane are underlined.
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