Chemistry Reference
In-Depth Information
protein biogenesis
transport
folding + ERAD
Ca
2
Ca
2
Ca
2
Ca
2+
Ca
2
+
Ca
2
IRE1
Ca
2
Ca
2
Ca
2
Ca
2+
Ca
2+
Ca
2
Ca
2
Ca
2
Ca
2+
Ca
2+
Ca
2
ATF6
Ca
2
PERK
UPR + apoptosis
Ca
2+
signaling
signal transduction
Fig. 9.1
Cross section through the ER, highlighting the central role of Sec61 complex and BiP
in protein biogenesis and calcium homeostasis in human cells.
ERAD
ER-associated protein deg-
radation,
SERCA
sarcoplasmic endoplasmic reticulum calcium ATPases,
UPR
unfolded protein
response
et al.
2012
). These contacts play important roles in cellular calcium homeostasis,
thus defining another major function of the mammalian ER. In addition, the ER
membrane forms a continuum with the outer nuclear envelope membrane.
Protein translocation into the ER is the first step in the biogenesis of many
proteins of eukaryotic cells (such as proteins of the ER, ERGIC, Golgi apparatus,
endosome, lysosome, nucleus, peroxisome, plasma membrane) as well as of most
extracellular proteins (Fig.
9.1
, “transport”) (Blobel and Dobberstein
1975a
,
b
).
Typically, protein translocation into the ER involves amino-terminal signal peptides
in the precursor polypeptides and a complex machinery of transport components,
most notably the heterotrimeric Sec61 complex in the ER-membrane and the ER-
lumenal Hsp70-type molecular chaperone BiP and its co-chaperones plus nucleo-
tide exchange factors or NEFs.
Protein transport into the ER is followed by folding and assembly of the newly
imported polypeptides (Fig.
9.1
, “folding”). Typically, this folding and assembly of
proteins involve some of the above-mentioned components, such as the calcium-
dependent chaperone BiP and its co-chaperones plus NEFs (Haas and Wabl
1983
;
Bole et al.
1986
; Weitzmann et al.
2007
; Zahedi et al.
2009
; Bulleid
2012
). Except for
resident proteins of the ER, the native proteins are delivered to their functional loca-
tion by vesicular transport (Schekman
2004
,
2005
; Sambrook
1990
; Pelham
1990
).
In cases of mis-folding or mis-assembly of polypeptides in the ER membrane or
lumen, the polypeptides are exported to the cytosol and degraded by the proteasome
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