Journal
JOURNAL OF CELL BIOLOGY
Volume 165, Issue 1, Pages 41-52Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200309132
Keywords
ER-associated degradation; misfolded proteins; protein folding; protein trafficking; endoplasmic reticulum
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Funding
- NIGMS NIH HHS [GM059171, R01 GM059171] Funding Source: Medline
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Misfolding proteins retained in the endoplasmic reticulum (ER) are degraded by the ER-associated degradation pathway. The mechanisms used to sort them from correctly folded proteins remain unclear. Analysis of substrates with defined folded and misfolded domains has revealed a system of sequential checkpoints that recognize topologically distinct domains of polypeptides. The first checkpoint examines the cytoplasmic domains of membrane proteins. If a lesion is detected, it is retained statically in the ER and rapidly degraded without regard to the state of its other domains. Proteins passing this test face a second checkpoint that monitors domains localized in the ER lumen. Proteins detected by this pathway are sorted from folded proteins and degraded by a quality control mechanism that requires ER-to-Golgi transport. Although the first checkpoint is obligatorily directed at membrane proteins, the second monitors both soluble and membrane proteins. Our data support a model whereby properly folded proteins are defined biologically as survivors that endure a series of distinct checkpoints.
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