MinireviewCore fucose and bisecting GlcNAc, the direct modifiers of the N-glycan core: their functions and target proteins
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Section snippets
Glycosyltransferases and N-glycan structure
It is well known that glycosylation affects many physicochemical properties of glycoproteins, such as conformation, flexibility, charge, and hydrophilicity. Thus, oligosaccharide modification affects biological processes including receptor activation, signal transduction, endocytosis, and cell adhesion, and leads to the regulation of many physiological and pathological events, including cell growth, migration, differentiation, tumor metastasis, and host–pathogen interactions.1, 2, 3, 4, 5, 6
EGFR
The epidermal growth factor receptor (EGFR) mediates the epidermal growth factor (EGF) and TGFα signalings, which stimulate cell growth and cell differentiation.18 The extracellular domain of EGFR contains 11 potential glycosylation sites, and it has been suggested that initial N-glycosylation is required for the proper sorting of EGFR to the membrane as well as for ligand binding.19, 20, 21, 22 Particularly, the N-glycan on Asn-420 functions to suppress ligand-independent spontaneous
E-cadherin
E-cadherin is a 120 kDa type I membrane protein, which belongs to the class of calcium-dependent cell-adhesion molecules.32 It mediates cell–cell adhesion through the assembly of multiprotein complexes linked to the actin cytoskeleton.33 The extracellular domain of human E-cadherin consists of five repeats of about 110 amino acid residues, referred to as EC1 through EC5, and contains four potential N-glycosylation sites, two each in EC4 and EC5. It is synthesized in the form of a precursor
Integrins
Integrins are a family of heterodimeric transmembrane receptors of the extracellular matrix.39 They consist of α and β subunits, each of which has a large extracellular region, a single transmembrane domain, and a short cytoplasmic domain (except for the β4 integrin). The N-terminal domains of the α and β subunits associate to form the integrin headpiece, which contains the extracellular matrix binding site. The C-terminal domains traverse the plasma membrane and mediate interactions with the
IgG
Most therapeutic antibodies that have been developed thus far are of the human IgG1 isotype. There are two N-linked glycosylation sites in the Fc region of human IgG. Biological activities referred to as ‘effector functions’ include antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through the interaction of the Fc with either Fcγ receptors or complement components. Recent studies have shown that manipulation of the N-glycan may yield optimized ADCC.
Other target proteins for Fut8 and GnT-III
To define the physiological role of Fut8 more clearly, we investigated Fut8-null mice and found that core fucosylation of the TGFβ receptor56 and LRP-157 affects their activity. A total of 70% of Fut8−/− mice died within three days after birth, and most of the survivors exhibited severe growth retardation and emphysema-like changes in the lungs. It was found that the activation of TGFβ receptors was downregulated in Fut8−/− cells.56 It was also observed that loss of core fucosylation of
Future perspective
As indicated above, core fucosylation and bisecting GlcNAc modulation of the N-glycans of the membrane protein could significantly alter their functions. It seems that signal regulation by an N-glycan structure often involves molecules that recognize the differences of oligosaccharides such as lectin-like molecules. It is also important to determine the conformational changes of glycoprotein caused by oligosaccharide modification. Integrated analysis of glycan from this new viewpoint will give
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