Biomedical Engineering Reference
In-Depth Information
some of its mechanistic principles are apparently shared with the
ERAD pathway [
24
], which transports misfolded proteins from
the ER to the cytosol to mediate their proteolytic degradation
(Fig.
1
, F).
4
Vesicular Transport
Along the secretory pathway, proteins are transported from the ER
via the Golgi to lysosomes, endosomes, the plasma membrane or
the extracellular space (Fig.
1
, G-M). How transport to autopha-
gosomes, peroxisomes, and lipid droplets is regulated is still a mat-
ter of debate, yet agreement has been reached on the involvement
of the ER as a starting point. The retrograde pathway—the endo-
cytic route—mediates the uptake of peptides, proteins, fl uids, and
nutrients from the extracellular space (Fig.
1
, N, O). Moreover,
the retrograde transport is critical for the recycling of components
of the transport machinery. Whereas the transport processes in
the early secretory pathway were studied in quite some detail, the
reactions by which autophagosomes, multivesicular bodies, peroxi-
somes, and lipid droplets exchange their constituents with other
compartments are still poorly understood and are intensely pur-
sued in current investigations (Tan et al., Chapter
10
;
Gireud et al.,
Chapter
9
; Wolinski and Kohlwein Chapter
21
;
Külzer et al.,
Chapter
5
;
Tooze et al., Chapter
12
)
.
Most of these transport steps occur via dedicated vesicles,
which serve as specialized transport carriers that shield their con-
tent form the cytoplasm. Transport vesicles are formed on a donor
membrane by the concerted action of small GTPases of the Arf/
Sar family and cytosolic coat proteins [
25
-
28
]. The coat proteins
can interact selectively with cargo proteins, either directly (in case
of membrane proteins) or via specialized membrane receptors [
9
,
29
,
30
]. These interactions in turn stabilize the soluble coat com-
ponents on the membrane, so that accumulations of cargo on the
luminal site of the membrane can induce the polymerization of the
coat on the cytosolic site. The formation of such coat complexes
lead to a deformation of the membrane either by their mechanical
properties, or by the sequestration of certain lipids which promote
the curvature of the membrane, or a combination of both mecha-
nisms [
31
-
34
]. The membrane deforming capacity of coat pro-
teins was fi rst demonstrated in the laboratory of Randy Schekman
by the formation of COPII-coated vesicles from synthetic, chemi-
cally defi ned liposomes [
35
]. Components of the COPII coat form
~70 nm vesicles at the ER membrane, which transport proteins to
the Golgi apparatus. Similar activities were reported for COPI
and clathrin coats, the two other major classes of coat complexes
[
36
-
38
]. The vesicles are fi nally pinched off from donor mem-
branes in a process which in some cases is facilitated by dynamin
