Biomedical Engineering Reference
In-Depth Information
There are two fundamentally different transport processes that
determine the fi nal location of any given protein: (1) Translocation,
which is the transport across or into the membranes of the ER or
other membrane-bound cellular organelles, like mitochondria,
chloroplasts, peroxisomes, and the nucleus and (2) Vesicle-mediated
transport processes between cellular compartments. The informa-
tion that sorts each polypeptide along its specifi c route is encoded
primarily within its sequence. Many of the signals that address pro-
teins to specifi c compartments of the secretory pathway are com-
plex and still not well understood, as next to the classical linear
motifs, multipartite signals also exist. Moreover, cargo receptors
and cofactors are often employed that create rather case specifi c
interaction surfaces. Therefore, these areas remain subjects of inten-
sive research (Hong Toh et al., Chapter
17
;
Tham et al., Chapter
16
;
Gee et al., Chapter
11
)
.
3
Protein Translocation
Only unfolded polypeptides can be translocated into the ER, mito-
chondria, and chloroplasts (Fig.
1
, A, B). Therefore, translocation
and protein synthesis often occur in a mechanistically and kinetically
coupled process [
11
-
13
]. To allow the initiation of translocation
before translation is completed, the targeting signals on these pro-
teins are typically positioned on their very N termini [
14
]. As soon as
these signals emerge from the ribosome, they are recognized by an
array of factors, which contribute to the processing, folding and/or
targeting of the newly synthesized proteins. Recent studies using
ribosome-profi ling or other high-throughput methods allowed the
proteome-wide identifi cation of the substrate specifi city of the differ-
ent ligands of the ribosomal exit tunnel [
15
-
18
]. Cargo is driven
across the translocases in a process that often relies on the activity of
chaperones, namely, that of members of the Hsp70 family [
19
-
21
].
Whereas the translocation machineries of the ER and of mitochon-
dria are studied extensively (Peleh et al., Chapter
3
; Becker et al.,
Chapter
2
)
, those of the chloroplast envelope membranes are still
poorly characterized. However, some recent studies have identifi ed a
large complex that presumably constitutes the translocase of the inner
membrane of chloroplasts (TIC) [
22
,
23
].
Nascent nuclear and peroxisomal proteins fold in the cytosol
and, hence, cross the membrane in a folded conformation (Fig.
1
,
C, D). The same is apparently true for some proteins that are trans-
ported through the plasma membrane (Fig.
1
, E) in a process
called unconventional secretion (Miura and Ueda, Chapter
4
). In
the case of the nucleus, the nuclear pore complex is large enough
to allow translocation of folded proteins and even of fully assem-
bled ribosomes. The translocation across peroxisomal membranes,
however, is still one of the big mysteries in cell biology. Interestingly,
