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 The export and 
degradation of misfolded ER proteins. 
Misfolded soluble proteins in the ER 
lumen are recognized and targeted 
to a translocator complex in the ER 
membrane. They first interact in the 
ER lumen with chaperones, disulfide 
isomerases, and lectins. The chaperones 
maintain the misfolded protein in an 
unfolded conformation and prevent their 
aggregation. The disulfide isomerases 
reduce disulfide bonds to fully unfold the 
protein. The lectins selectively recognize 
trimmed N-linked oligosaccharides that 
are generated when a protein spends 
too long in the ER. The lectins have 
binding sites on a membrane-embedded 
protein translocator built around an E3 
ubiquitin ligase. The unfolded protein is 
then exported into the cytosol through 
the translocator. The E3 ubiquitin ligase 
ubiquitylates the unfolded protein as it 
emerges on the cytosolic side of the 
translocator. The ubiquitin prevents 
backsliding of the protein into the ER 
and provides a molecular handle for 
an AAA-ATPase that completes the 
extraction reaction. The unfolded protein 
is then de-glycosylated and degraded 
in proteasomes. Misfolded membrane 
proteins follow a similar pathway but 
are thought to engage the translocator 
sideways within the lipid bilayer. Multiple 
translocator complexes containing different 
E3 ubiquitin ligases reside in the ER.  
They are thought to handle different 
subsets of proteins that are misfolded in 
different ways.