CDH1 (E-cadherin) is N-glycosylated at asparagine residue...

CDH1 (E-cadherin) is N-glycosylated at asparagine residues N558, N570, N622, and N637 (labeled as N554, N566, N618, and N633 in 2008 publications - possibly due to erroneous reference sequence at the time) (Zhao et al. 2008; Zhou et al. 2008). Two of these four asparagine residues, N558 and N570, belong to the Cadherin 4 repeat, and two, N622 and N637, to the Cadherin 5 repeat in the extracellular region of CDH1 according to the UniProt annotation of CDH1 domains (UniProt Consortium 2025). All four glycosylated asparagines in CDH1 conform with the glycosylation sequon Asn-X-Thr/Ser which is glycosylated in the endoplasmic reticulum (ER) through transfer of the preassembled, high-mannose oligosaccharide (GlcNAc)₂-(Man)₉-(Glc)₃, Glu3Man9GlucNAc2 glycan for short, from a dolichyl-pyrophosphate carrier by the oligosaccharyltransferase (OST) complex (Ramírez et al. 2019). Of the two OST complexes, OST-A and OST-B, the OST-A glycosylates unfolded proteins while OST-B glycosylates partially folded proteins with disulfide bonds (Ramírez et al. 2019). Since N-glycosylation of CDH1 on four asparagine residues, and N637 in particular, is required for proper folding and translocation of CDH1 to Golgi for further processing (Zhou et al. 2008), it is likely that the glycosylation step is performed by the OST-A complex. In Drosophila, it was shown that the glucosyltransferase Xiantuan (also known as xit, a homologue of yeast ALG8), which encodes one of the enzymes involved in the addition of the terminal glucose residues to the Glu3Man9GlucNAc2 glycan precursor, is required for the proper glycosylation and intracellular distribution of E-cadherin (Zhang et al. 2014).

Three glycosylated asparagine residues, N558, N622, and N637, are conserved between mouse, dog, and human (Liwosz et al. 2006: in this study, residues are numbered using mature CDH1 coordinates, after the removal of the pro-peptide which ends at the amino acid residue 154 of the nascent protein, and are therefore listed as N404, N468, and N483). Simultaneous substitution of N558 and N622, or N622 and N637, or all three N558, N622, and N637, with glutamine (Gln) residues, results in severe reduction of CDH1 protein expression (Liwosz et al. 2006). The core glycan added to target CDH1 asparagine residues is subsequently further modified in a cell density-dependent manner, which affects the molecular organization and stability of CDH1 junctions (Liwosz et al. 2006).