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First published online October 30, 2006
doi: 10.1242/10.1242/jcs.03225
Commentary |
1 Biocenter Oulu and Department of Biochemistry, University of Oulu, FIN-90014 Oulu, Finland
2 Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
* Author for correspondence (e-mail: maurizio.molinari{at}irb.unisi.ch)
Accepted 23 August 2006
Glycosylation of asparagine residues in Asn-x-Ser/Thr motifs is a common covalent modification of proteins in the lumen of the endoplasmic reticulum (ER). By substantially contributing to the overall hydrophilicity of the polypeptide, pre-assembled core glycans inhibit possible aggregation caused by the inevitable exposure of hydrophobic patches on the as yet unstructured chains. Thereafter, N-glycans are modified by ER-resident enzymes glucosidase I (GI), glucosidase II (GII), UDP-glucose:glycoprotein glucosyltransferase (UGT) and mannosidase(s) and become functional appendices that determine the fate of the associated polypeptide. Recent work has improved our understanding of how the removal of terminal glucose residues from N-glycans allows newly synthesized proteins to access the calnexin chaperone system; how substrate retention in this specialized chaperone system is regulated by de-/re-glucosylation cycles catalyzed by GII and UGT1; and how acceleration of N-glycan dismantling upon induction of EDEM variants promotes ER-associated degradation (ERAD) under conditions of ER stress. In particular, characterization of cells lacking certain ER chaperones has revealed important new information on the mechanisms regulating protein folding and quality control. Tight regulation of N-glycan modifications is crucial to maintain protein quality control, to ensure the synthesis of functional polypeptides and to avoid constipation of the ER with folding-defective polypeptides.
Key words: ER, N-glycans, Protein folding, Quality control, ER-associated degradation, calnexin, EDEM
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