Glycoprotein Tertiary and Quaternary Structures Are Monitored by the Same Quality Control Mechanism

Keith, Natasha; Parodi, Armando J.; Caramelo, Julio J.

doi:10.1074/jbc.m501710200

Cited by 41 publications

(33 citation statements)

References 18 publications

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“…GT may also glucosylate glycoproteins in not fully assembled oligomeric complexes because it also recognizes hydrophobic surfaces exposed as a consequence of the absence of subunit components (6). The aim of this review is to give an overview of recent reports dealing with the entrance and exit of glycoproteins from CNX/CRT cycles.…”

mentioning

confidence: 99%

Getting In and Out from Calnexin/Calreticulin Cycles

Caramelo

Parodi

2008

Journal of Biological Chemistry

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269

229

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The N-glycan-dependent quality control mechanism of glycoprotein folding was proposed initially by Helenius and coworkers several years ago; with a few minor modifications, it is still valid today ( Fig. 1) (1-3).2 Glycan processing starts immediately after its transfer from a dolichol-P-P derivative to Asn residues in nascent polypeptide chains entering the lumen of the ER. 3 Removal of the outermost and following glucoses by the successive action of GI and GII exposes the Glc 1 Man 9 GlcNAc 2 epitope (Fig. 2). This structure is then recognized by two ER resident lectins (CNX and CRT) that specifically bind monoglucosylated polymannose glycans. This is followed by removal of the innermost glucose by GII, thus liberating the glycoprotein from the lectin anchor. The proteinlinked glycan is then reglucosylated by the soluble ER enzyme GT only if the protein moiety displays non-native three-dimensional structures, as this enzyme behaves as a conformational sensor. Cycles of CNX/CRT-glycoprotein binding and liberation, catalyzed by the opposing activities of GT and GII, are terminated once glycoproteins attain their native structures. Glucose-free glycoproteins then continue their transit through the secretory pathway. Alternatively, permanently misfolded glycoproteins may be then transported to the cytosol for proteasomal degradation. Lectin-glycoprotein association not only thwarts Golgi exit of folding intermediates and irreparably misfolded glycoproteins but also enhances folding efficiency by preventing aggregation and promoting proper disulfide bonding. The latter is catalyzed by an oxidoreductase of the proteindisulfide isomerase family (ERp57) that acts exclusively on glycoproteins, as it is loosely associated with CNX/CRT.GT is the only component of the quality control mechanism that senses protein conformations, as it recognizes hydrophobic amino acid patches exposed in molten globule-like conformers (4, 5). GT may also glucosylate glycoproteins in not fully assembled oligomeric complexes because it also recognizes hydrophobic surfaces exposed as a consequence of the absence of subunit components (6). The aim of this review is to give an overview of recent reports dealing with the entrance and exit of glycoproteins from CNX/CRT cycles. Getting In: GII Is Not What It Was Thought to BeThe first step in the pathway leading to the entrance of glycoproteins into CNX/CRT cycles is the removal of the outermost glucose unit from the glycan by the membrane enzyme GI. This reaction occurs almost simultaneously with glycan transfer. The rapid GI-mediated deglucosylation of the protein-linked glycan, as well as the apparent inability of the enzyme to remove in vivo (but not in vitro) the glucose from the dolichol-P-P-linked glycan, strongly suggests the existence of a supercomplex formed by the oligosaccharyltransferase, GI, and the dolichol derivative, with a very precise orientation of the components.It was assumed that the sole role of GII was that of removing glucose residues l and n (Fig. 2). Recent work has sugg...

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mentioning

confidence: 99%

Getting In and Out from Calnexin/Calreticulin Cycles

Caramelo

Parodi

2008

Journal of Biological Chemistry

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269

229

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“…Increase in ANS binding caused by the dissociation of soybean agglutinin (a homotetrameric complex having one N-glycan per monomer) upon addition of increasing urea concentrations was shown to parallel an increase in GT mediated glucosylation [31]. Furthermore, reassociation of the monomers upon withdrawing urea also resulted in a concomitant decrease in GT activity.…”

Section: Protein Determinants Recognized By Gtmentioning

confidence: 89%

How sugars convey information on protein conformation in the endoplasmic reticulum

Caramelo

Parodi

2007

Seminars in Cell & Developmental Biology

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The N-glycan-dependent quality control of glycoprotein folding prevents endoplasmic reticulum to Golgi exit of folding intermediates, irreparably misfolded glycoproteins and not completely assembled multimeric complexes. It also enhances folding efficiency by preventing aggregation and facilitating formation of proper disulfide bonds. The control mechanism essentially involves four components, resident lectin-chaperones that recognize monoglucosylated polymannose glycans, a lectin-associated oxidoreductase acting on monoglucosylated glycoproteins, a glucosyltransferase and a glucosidase that creates monoglucosylated epitopes in glycans transferred in protein Nglycosylation or removes the glucose units added by the glucosyltransferase. This last enzyme is the only mechanism component sensing glycoprotein conformations as it creates monoglucosylated glycans exclusively in not properly folded species or in not completely assembled complexes The purpose of the review is to describe the most significant recent findings on the mechanism of glycoprotein folding and assembly quality control and to discuss the main still unanswered questions.

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“…Caramelo and co-workers used SBA to study how does UGGT recognize oligomeric proteins (25). The native SBA homotetramer is a very poor substrate of UGGT.…”

Section: B Uggt Assay and Analytical Methods To Characterize Glycoprmentioning

confidence: 99%

Misfolded Glycoproteins as Probes for Analysis of Folding Sensor Enzyme UDP-Glucose

Izumi

Kiuchi

Ito

et al. 2013

TIGG

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Glycoprotein Tertiary and Quaternary Structures Are Monitored by the Same Quality Control Mechanism

Cited by 41 publications

References 18 publications

Getting In and Out from Calnexin/Calreticulin Cycles

Getting In and Out from Calnexin/Calreticulin Cycles

How sugars convey information on protein conformation in the endoplasmic reticulum

Misfolded Glycoproteins as Probes for Analysis of Folding Sensor Enzyme UDP-Glucose

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