Misfolded Proteins Are Sorted by a Sequential Checkpoint Mechanism of ER Quality Control

• Published in: The Journal of cell biology Vol. 165; no. 1; pp. 41 - 52
• Main Authors: Vashist, Shilpa, Davis T. W. Ng
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 12-04-2004; The Rockefeller University Press
• Subjects: Cells; Cellular biology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Glycoproteins; Golgi apparatus; Golgi Apparatus - metabolism; Golgi Apparatus - ultrastructure; Intracellular Membranes - metabolism; Lesions; Mannosidases - metabolism; Membrane proteins; Membrane Proteins - metabolism; Misfolded proteins; Molecular Chaperones - metabolism; P branes; Peptides; Peptides - metabolism; Protein Folding; Protein Processing, Post-Translational - physiology; Protein Structure, Tertiary - physiology; Protein Transport - physiology; Proteins - metabolism; Quality assurance; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae - ultrastructure; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction - physiology; Yeasts
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200309132

Misfolded 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.