Beta1,4-N-Acetylgalactosaminyltransferase-3 (B4GALNT3) and Beta1,4-N-Acetylgalactosaminyltransferase-4 (B4GALNT4)

Abstract

N- and O-glycans terminating with GalNAcβ1-4GlcNAcβ (LacdiNAc) occur on a number of glycoproteins including lutropin (LH) (Green et al. 1985), thyrotropin (TSH) (Baenziger and Green 1991), prolactin-like proteins (Manzella et al. 1997), glycodelin (Dell et al. 1995), tissue factor pathway inhibitor (Smith et al. 1992), carbonic anhydrase 6 (Hooper et al. 1995), SorLA/LR11 (Fiete et al. 2007), zona pellucida 3 (Dell et al. 2003), and extracellular matrix glycoproteins (Breloy et al. 2012). The β1,4-linked GalNAc can be further modified with a variety of moieties: 4-linked SO₄ (Baenziger and Green 1991) and α2,6-linked N-acetylneuraminic acid (NANA) (Stockell Hartree and Renwick 1992), or the subterminal GlcNAc can be modified with α1,3-linked fucose to form GalNAcβ1,4(Fucα1,3)GlcNAcβ (Dell et al. 1995) or in the case of core 2 O-linked structures with PO₄ (Breloy et al. 2012). Each of these structures is unique by virtue of the presence of the β1,4-linked GalNAc rather than the more common β1,4-linked Gal. The presence of LacdiNAc on the N-glycans of LH, TSH, and the free glycoprotein hormone α-subunit and its absence on N-glycans of follitropin (FSH) and other glycoproteins synthesized in the pituitary led to the hypothesis that the β1,4-N-acetylgalactosaminyltransferase (β4GalNAc-T) responsible for the synthesis of these structures is protein specific (Baenziger and Green 1988). A β4GalNAc-T with the predicted protein specificity was demonstrated in pituitary extracts (Smith and Baenziger 1988), and key residues essential for the recognition of the glycoprotein hormones were identified (Mengeling et al. 1995). Two β1,4-N-acetylgalactosaminyltransferases, β4GalNAc-T3 (Sato et al. 2003) and β4GalNAc-T4 (Gotoh et al. 2004) were cloned and shown to transfer GalNAc to β-linked GlcNAc to form LacdiNAc-containing structures on N- and O-linked glycans such as those shown in Fig. 40.1. β4GalNAc-T3 and β4GalNAc-T4 recognize peptide sequences that result in protein-specific modification of N- and O-glycans (Fiete et al. 2012a, b; Miller et al. 2008) and display the specificity predicted for the β4GalNAc-T activity responsible for the modification of the LH N-glycans. β4GalNAc-T3 and β4GalNAc-T4 transcripts are present in a number of tissues, suggesting that other glycoproteins will be specifically modified with glycans containing LacdiNAc and that as with the glycoprotein hormones the presence of LacdiNAc will be of biologic importance for the function of these glycoproteins.