Redox-dependent protein quality control in the endoplasmic reticulum: folding to degradation.
CONCLUSIONS
Nascent polypeptides entering the endoplasmic reticulum (ER) are co- and post-translationally modified by N-glycosylation and the oxidation/isomerization of cysteine residues followed by folding with the aid of molecular chaperones. Only properly folded proteins reach their final destination. The oxidative environment in the ER enables ER-resident oxidoreductases to facilitate disulfide bond formation, which stabilizes protein structures. ER oxidoreductases involve in both the productive folding of newly synthesized proteins and ER-associated degradation (ERAD) of misfolded proteins.


BACKGROUND
The ER luminal event of ERAD is composed of three major steps: the recognition and segregation of terminally misfolded proteins from folding intermediates, unfolding of misfolded substrates by oxidoreductases that cleave the disulfide bonds to enable the translocation of the substrates through the retrotranslocation channel, and transport of substrates to be degraded to the dislocon channel. The factors required for these three critical steps have been found to form a supramolecular complex in the ER.


RESULTS
This complex comprises EDEM1, a lectin-like molecule that recognizes mannose-trimming and segregates the identified substrates from the productive folding pathway into the degradation pathway; ER DnaJ (ERdj)5, a reductase that resides in the ER and reduces disulfides in misfolded proteins; and immunoglobulin heavy chain binding protein (BiP), an heat shock protein (Hsp)70 family molecular chaperone that recruits substrates to the dislocon channel after dissociation from the EDEM1/ERdj5 complex coupled with ATP hydrolysis.


CONCLUSIONS
The importance of disulfide bond reduction in misfolded proteins for retrotranslocation through the dislocon channel will be discussed by comparing the function of ERdj5 with that of other oxidoreductases in the ER.
Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kyoto-City, Japan.
Masatoshi
M
Hagiwara
Kazuhiro
K
Nagata
D004721:Endoplasmic Reticulum / Q000378:metabolism*; D060746:Endoplasmic Reticulum-Associated Degradation; D006031:Glycosylation; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism*
D011506:Proteins; D010088:Oxidoreductases