Published online June 23, 2008
doi:10.1083/jcb.200804053
The Journal of Cell Biology, Vol. 181, No. 7, 1095-1105
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Scott et al.
Role of Sec61p in the ER-associated degradation of short-lived transmembrane proteins
Daniel C. Scott and
Randy Schekman
Department of Molecular and Cell Biology and Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720
Correspondence to Randy Schekman: schekman{at}berkeley.edu
Misfolded proteins in the endoplasmic reticulum (ER) are identified and degraded by the ER-associated degradation pathway (ERAD), a component of ER quality control. In ERAD, misfolded proteins are removed from the ER by retrotranslocation into the cytosol where they are degraded by the ubiquitin–proteasome system. The identity of the specific protein components responsible for retrotranslocation remains controversial, with the potential candidates being Sec61p, Der1p, and Doa10. We show that the cytoplasmic N-terminal domain of a short-lived transmembrane ERAD substrate is exposed to the lumen of the ER during the degradation process. The addition of N-linked glycan to the N terminus of the substrate is prevented by mutation of a specific cysteine residue of Sec61p, as well as a specific cysteine residue of the substrate protein. We show that the substrate protein forms a disulfide-linked complex to Sec61p, suggesting that at least part of the retrotranslocation process involves Sec61p.
D.C. Scott's current address is Depts. of Structural Biology and Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Abbreviations used in this paper: 
f, -factor; CPY, carboxypeptidase Y; ERAD, ER-associated degradation.
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