Protein N-Glycosylation, Protein Folding, and Protein Quality Control

Abstract

Quality control of protein folding represents a fundamental cellular activity. Early steps of protein N-glycosylation involving the removal of three glucose and some specific mannose residues in the endoplasmic reticulum have been recognized as being of importance for protein quality control. Specific oligosaccharide structures resulting from the oligosaccharide processing may represent a glycocode promoting productive protein folding, whereas others may represent glyco-codes for routing not correctly folded proteins for dislocation from the endoplasmic reticulum to the cytosol and subsequent degradation. Although quality control of protein folding is essential for the proper functioning of cells, it is also the basis for protein folding disorders since the recognition and elimination of non-native conformers can result either in loss-of-function or pathological-gain-of-function. The machinery for protein folding control represents a prime example of an intricate interactome present in a single organelle, the endoplasmic reticulum. Here, current views of mechanisms for the recognition and retention leading to productive protein folding or the eventual elimination of misfolded glycoproteins in yeast and mammalian cells are reviewed.

Biological and Structural Characterization of Glycosylation on Ephrin-A1, a Preferred Ligand for EphA2 Receptor Tyrosine Kinase

“…On the other hand, enzymatic deglycosylation of the properly folded eA1-WT resulted in a soluble, aggregate-free protein. Thus, it appears that eA1 glycosylation is also essential for the correct folding of the protein (34).…”

Carboxypeptidase X-1 (CPX-1) is a secreted collagen-binding glycoprotein

“…As N-glycosylation has been shown to be essential for efficient secretion of some but not all N-glycosylated proteins [14] we first determined whether N-glycosylation was required for efficient secretion of CPX-1. Human CPX- Fig 1C).…”

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

“…N‐glycosylation is important for the formation of mature glycoproteins in eukaryotes 1. Class I α‐1, 2‐mannosidases are important for Asn‐linked oligosaccharide maturation in the endoplasmic reticulum (ER) and Golgi complex 2.…”

“…These modifications affect cell growth, cell–cell adhesion, cell motility, and protein phosphorylation. The activity of the enzymes involved in N‐glycosylation must therefore be tightly regulated because N‐glycan composition determines the fate of the protein, including whether or not the protein will be folded in the ER lumen or retrotranslocated into the cytosol and degraded 1, 5. Hence, α‐1,2‐mannosidases are not only involved in protein folding but also play a role in misfolded protein degradation 6…”