A sweet code for glycoprotein folding

Abstract

a b s t r a c tGlycoprotein synthesis is initiated in the endoplasmic reticulum (ER) lumen upon transfer of a glycan (Glc 3 Man 9 GlcNAc 2 ) from a lipid derivative to Asn residues (N-glycosylation). N-Glycan-dependent quality control of glycoprotein folding in the ER prevents exit to Golgi of folding intermediates, irreparably misfolded glycoproteins and incompletely 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 (calnexin and calreticulin) that recognize monoglucosylated polymannose protein-linked glycans, lectin-associated oxidoreductase acting on monoglucosylated glycoproteins (ERp57), a glucosyltransferase that creates monoglucosylated epitopes in protein-linked glycans (UGGT) and a glucosidase (GII) that removes the glucose units added by UGGT. This last enzyme is the only mechanism component sensing glycoprotein conformations as it creates monoglucosylated glycans exclusively in not properly folded glycoproteins or in not completely assembled multimeric glycoprotein complexes. Glycoproteins that fail to properly fold are eventually driven to proteasomal degradation in the cytosol following the ER-associated degradation pathway, in which the extent of N-glycan demannosylation by ER mannosidases play a relevant role in the identification of irreparably misfolded glycoproteins.

N-linked glycosylation and homeostasis of the endoplasmic reticulum

“…The CNX/CRT cycle for glycoprotein quality control is the subject of two excellent recent reviews [1,2]. Unfolded nascent glycoproteins have GlcNAc 2 Man 9 Glc 3 oligosaccharides (abbreviated as GN 2 M 9 G 3 , see Fig.…”

“…OS-9 and XTP3-B promote delivery of unfolded glycoproteins to the HRD1-SEL1 complex (Fig. 2g) for ER associated degradation (ERAD) (as reviewed by [2,3]). Thus, both the protein folding branch and the protein degradation branch of the glycoprotein quality control pathway are dependent upon the accurate and efficient addition of the fully assembled N-linked oligosaccharides to nascent proteins.…”

Mannosidase IA is in Quality Control Vesicles and Participates in Glycoprotein Targeting to ERAD

“…Alternatively, if the glycan is glucosylated or if it was first trimmed by ERManI or EDEM2 (which have higher specificity for Man B), ManIA could remove Man C, which would allow binding to OS-9 and targeting to ERAD. However, this would require dissociation from CNX, and removal of Man C strongly decreases sensitivity to glucosidase II [1,30,31], which would prevent the glycoprotein from being deglucosylated and leaving the CNX cycle. Altogether, ManIA would tend to prolong the permanence in the CNX folding cycle of a glycoprotein molecule that is preferentially glucosylated (a good substrate of UDP-Glc:glycoprotein glucosyltransferase) and remove one that is not glucosylated, targeting it to ERAD.…”

“…For glycoproteins, their precursor N-glycans, with the structure Glc 3 Man 9 GlcNAc 2 , undergo sequential trimming reactions that allow their binding to a series of lectins that participate in the folding and quality control. Excision of two Glc residues allows association with calnexin (CNX) or calreticulin [1,2]. Removal of the innermost Glc and of Man A (Fig.…”

Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies

“…Those substrates can be targeted for degradation in different ways, including exposure of hydrophobic degrons that would be otherwise buried inside the protein or post-translational polyglycosylation of Asn residues. In the latter case, misfolded proteins are signaled for endoplasmic reticulum-associated protein degradation (ERAD) [6].…”