Key Points
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Protein folding in the endoplasmic reticulum (ER) is assisted by several molecular chaperones and folding factors. These proteins are key players in the quality-control (QC) system, which regulates the transport of proteins from the ER to other compartments of the secretory pathway.
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The QC system works at two levels — general and protein-specific. The general level ('primary QC') applies to all proteins and involves the recognition of structural and biophysical features that are common to non-native proteins. The protein-specific level ('secondary QC') involves the recognition of individual proteins or protein families by specialized chaperones.
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An important factor for determining ER retention is protein stability — the lower the overall stability of a protein the more likely it is to be retained.
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For glycoproteins, there is a QC system that is based on the recognition of specific glycosylation intermediates of N-linked glycans. This system depends crucially on the direct interaction of the two lectin chaperones, calnexin and calreticulin, with newly synthesized glycoproteins.
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At the level of ER export, protein sorting at ER exit sites determines whether a protein can leave the ER. Here, export and retention signals, the effects of protein mobility in the ER and selective inclusion in ER exit sites are crucial factors.
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Protein folding and maturation are intrinsically error-prone processes, and a substantial fraction of proteins are degraded rapidly after synthesis. Peptides from degraded proteins are presented on the cell-surface and thereby ensure the early detection of, for example, viral infections.
Abstract
The endoplasmic reticulum (ER) has a quality-control system for 'proof-reading' newly synthesized proteins, so that only native conformers reach their final destinations. Non-native conformers and incompletely assembled oligomers are retained, and, if misfolded persistently, they are degraded. As a large fraction of ER-synthesized proteins fail to fold and mature properly, ER quality control is important for the fidelity of cellular functions. Here, we discuss recent progress in understanding the conformation-specific sorting of proteins at the level of ER retention and export.
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Acknowledgements
We thank A. Smith, A. Mezzacasa and E. Frickel for their critical reading of the manuscript. This work was supported by the Swiss National Science Foundation.
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DATABASES
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UDP-glucose:glycoprotein glucosyltransferase
FURTHER INFORMATION
Glossary
- CONFORMATIONAL STABILITY
-
The conformational stability of a protein is defined as the free energy change, ΔG, for the conversion of its unfolded (denatured) form to its folded (native) form.
- LECTIN
-
A protein that binds carbohydrates.
- F-BOX PROTEIN
-
A protein component of a ubiquitin-ligase complex that contains an F-box domain, which is responsible for the interaction with a specific substrate protein.
- UBIQUITIN LIGASE
-
A protein or protein complex that mediates the ubiquitylation of a substrate protein through interactions with other components of the ubiquitylation machinery.
- CFTR
-
(Cystic fibrosis transmembrane conductance regulator). A plasma membrane Cl− channel.
- CFTRΔF508
-
A folding-defective and principal disease-causing allele of the cystic fibrosis transmembrane conductance regulator (CFTR).
- TYPE I MEMBRANE PROTEIN
-
A transmembrane protein that is orientated with its carboxyl terminus in the cytosol.
- 14-3-3 PROTEINS
-
A family of abundant proteins that bind to phosphoserine- and phosphothreonine-containing motifs in a sequence-specific manner.
- INVARIANT CHAIN
-
A specific chaperone and escort protein for MHC class II molecules.
- TYPE II MEMBRANE PROTEIN
-
A transmembrane protein that is orientated with its amino terminus in the cytosol.
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Ellgaard, L., Helenius, A. Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 4, 181–191 (2003). https://doi.org/10.1038/nrm1052
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DOI: https://doi.org/10.1038/nrm1052
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