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Emerging structural insights into glycoprotein quality control coupled with N-glycan processing in the endoplasmic reticulum.

ABSTRACT: In the endoplasmic reticulum (ER), the sugar chain is initially introduced onto newly synthesized proteins as a triantennary tetradecasaccharide (Glc3Man9GlcNAc2). The attached oligosaccharide chain is subjected to stepwise trimming by the actions of specific glucosidases and mannosidases. In these processes, the transiently expressed N-glycans, as processing intermediates, function as signals for the determination of glycoprotein fates, i.e., folding, transport, or degradation through interactions of a series of intracellular lectins. The monoglucosylated glycoforms are hallmarks of incompletely folded states of glycoproteins in this system, whereas the outer mannose trimming leads to ER-associated glycoprotein degradation. This review outlines the recently emerging evidence regarding the molecular and structural basis of this glycoprotein quality control system, which is regulated through dynamic interplay among intracellular lectins, glycosidases, and glycosyltransferase. Structural snapshots of carbohydrate-lectin interactions have been provided at the atomic level using X-ray crystallographic analyses. Conformational ensembles of uncomplexed triantennary high-mannose-type oligosaccharides have been characterized in a quantitative manner using molecular dynamics simulation in conjunction with nuclear magnetic resonance spectroscopy. These complementary views provide new insights into glycoprotein recognition in quality control coupled with N-glycan processing.

SUBMITTER: Satoh T

PROVIDER: S-EPMC6272264 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Emerging structural insights into glycoprotein quality control coupled with N-glycan processing in the endoplasmic reticulum.

Satoh Tadashi T Yamaguchi Takumi T Kato Koichi K

Molecules (Basel, Switzerland) 20150130 2

In the endoplasmic reticulum (ER), the sugar chain is initially introduced onto newly synthesized proteins as a triantennary tetradecasaccharide (Glc3Man9GlcNAc2). The attached oligosaccharide chain is subjected to stepwise trimming by the actions of specific glucosidases and mannosidases. In these processes, the transiently expressed N-glycans, as processing intermediates, function as signals for the determination of glycoprotein fates, i.e., folding, transport, or degradation through interacti ...[more]

PMID: 25647580

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Project description:The endoplasmic reticulum (ER) is the subcellular site where proteins following the secretory pathway acquire their proper tertiary and, in certain cases, quaternary structures. Species that are not yet properly folded are prevented from exit to the Golgi apparatus and, if permanently misfolded, are transported to the cytosol, where they are degraded in the proteasomes. This review deals with a mechanism, applicable to proteins that are N-glycosylated in the ER, by which the quality control of folding is performed. Protein-linked monoglucosylated glycans, formed by glucosidase I- and glucosidase II-dependent partial deglucosylation of the oligosaccharides transferred from dolichol diphosphate derivatives in N-glycosylation (Glc(3)Man(9)GlcNAc(2)), mediate glycoprotein recognition by two ER-resident lectins, membrane-bound calnexin (CNX) and its soluble homologue, calreticulin (CRT). A still not yet fully confirmed interaction between the lectins and the protein moieties of folding glycoproteins may occur after lectin recognition of monoglucosylated structures. Further deglucosylation of glycans by glucosidase II, and perhaps also by a change in CNX/CRT and/or in the substrate glycoprotein conformation, liberates the glycoproteins from their CNX/CRT anchors. Glycans may be then reglucosylated by the UDP-Glc:glycoprotein glucosyltransferase (GT), and thus be recognized again by CNX/CRT, but only when linked to not yet properly folded protein moieties, as this enzyme behaves as a sensor of glycoprotein conformation. Deglucosylation/reglucosylation cycles catalysed by the opposing activities of glucosidase II and GT only stop when proper folding is achieved. The interaction between CNX/CRT and a monoglucosylated glycan is one of the alternative mechanisms by which cells retain not yet properly folded glycoproteins in the ER; in addition, it enhances folding efficiency by preventing protein aggregation and thus allowing intervention of classical chaperones and other folding-assisting proteins. There is evidence suggesting that both glycoprotein glucosylation and mannose removal, respectively mediated by GT and ER mannosidase I, might be involved in cell recognition of permanently misfolded glycoproteins bound for proteasome degradation.

Dataset Information

Emerging structural insights into glycoprotein quality control coupled with N-glycan processing in the endoplasmic reticulum.

Publications

Emerging structural insights into glycoprotein quality control coupled with N-glycan processing in the endoplasmic reticulum.

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