The evolution of N-glycan-dependent endoplasmic reticulum quality control factors for glycoprotein folding and degradation

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology, Department of Neurobiology University of Massachusetts Medical School



Document Type


Medical Subject Headings

Animals; Carbohydrate Sequence; Endoplasmic Reticulum; Entamoeba histolytica; *Evolution, Molecular; Glycoproteins; Mannosidases; Molecular Sequence Data; Plasmodium falciparum; Polysaccharides; Predictive Value of Tests; Proteasome Endopeptidase Complex; *Protein Folding; Protozoan Proteins; Saccharomyces cerevisiae Proteins; Trichomonas


Asn-linked glycans (N-glycans) play important roles in the quality control (QC) of glycoprotein folding in the endoplasmic reticulum (ER) lumen and in ER-associated degradation (ERAD) of proteins by cytosolic proteasomes. A UDP-Glc:glycoprotein glucosyltransferase glucosylates N-glycans of misfolded proteins, which are then bound and refolded by calreticulin and/or calnexin in association with a protein disulfide isomerase. Alternatively, an alpha-1,2-mannosidase (Mns1) and mannosidase-like proteins (ER degradation-enhancing alpha-mannosidase-like proteins 1, 2, and 3) are part of a process that results in the dislocation of misfolded glycoproteins into the cytosol, where proteins are degraded in the proteasome. Recently we found that numerous protists and fungi contain 0-11 sugars in their N-glycan precursors versus 14 sugars in those of animals, plants, fungi, and Dictyostelium. Our goal here was to determine what effect N-glycan precursor diversity has on N-glycan-dependent QC systems of glycoprotein folding and ERAD. N-glycan-dependent QC of folding (UDP-Glc:glycoprotein glucosyltransferase, calreticulin, and/or calnexin) was present and active in some but not all protists containing at least five mannose residues in their N-glycans and was absent in protists lacking Man. In contrast, N-glycan-dependent ERAD appeared to be absent from the majority of protists. However, Trypanosoma and Trichomonas genomes predicted ER degradation-enhancing alpha-mannosidase-like protein and Mns1 orthologs, respectively, each of which had alpha-mannosidase activity in vitro. Phylogenetic analyses suggested that the diversity of N-glycan-dependent QC of glycoprotein folding (and possibly that of ERAD) was best explained by secondary loss. We conclude that N-glycan precursor length has profound effects on N-glycan-dependent QC of glycoprotein folding and ERAD.

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Citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11676-81. Epub 2007 Jul 2. Link to article on publisher's site

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Link to Article in PubMed