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A family of UDP-GalNAc: polypeptide N-acetylgalactosaminyl-transferases control the initiation of mucin-type O-linked glycosylation.

Enzymatic glycosylation of proteins involves the addition of a monosaccharide or, in the case of N-linked glycosylation of asparagine, a preformed oligosaccharide to an amino acid in a given protein. The initial step of protein glycosylation is an important event in the formation of a given glycopeptide linkage (glycoconjugate type), which involves essential recognition events between the protein and glycosyltransferase that determine the specific sites of glycan attachment. Complete processing and extension of glycan chains involves the cooperative action of perhaps hundreds of different glycosyltransferases, which successively add monosaccharides to the growing glycan chain. The characterization of glycan structures on glycoproteins as well as the identification of specific sites of glycan attachment are important for understanding the structure of a given glycoprotein, its function, and its immunobiology (Lis et al., 1993; Varki, 1993; Parekh, 1994). Mucin-type O-glycosylation is initiated by the enzyme UDP-N-acetylgalactosamine: polypeptide yV-acetylgalactosaminyltransferase (GalNAc-transferase) (EC. 2.4.1.41). In this reaction GalNAc (derived from the donor substrate UDPGalNAc) is transferred to the side chains of serine and threonine residues on polypeptides. This reaction, which has been named mucin-type O-glycosylation because of its preponderance on mucin-like glycoproteins, is one of the most abundant forms and means of glycosylation found in animals and is not restricted to mucin-like glycoproteins. This review will cover recent developments in our understanding of a family of GalNAc-transferases that mediate this type of protein glycosylation. Mucin-type glycosylation is an important post-translational modification of many animal proteins. Alterations in the Oglycosylation patterns of some proteins may play a role in the pathogenesis of several diseases in which there is evidence for altered glycoprotein structure, including ulcerative colitis, chronic bronchitis, cystic fibrosis, and cancer (Varki, 1993). In addition to its structural and functional importance to mucins, in which O-linked carbohydrates may constitute up to 80% of the total mass of these glycoproteins, O-glycosylation has been shown to be important to the folding of proteins such as hCG3, and the conformation and protease resistance of 'stem regions' of membrane-bound proteins. Mucin-like domains are also found on cell surface associated molecules functioning as selectin ligands (e.g., PSGL-1, MadCAM, CD-34; see Varki, 1993). A long-standing puzzle has been what determines sites of O-glycosylation. This is an important question because of evidence that spacing of O-glycans on many glycoproteins may be important to their function (Springer, 1994). The molecular processes governing the specificity and kinetics of mucin-type O-linked glycosylation and the parallel Man-type glycosylation of serine/threonine in yeast are poorly understood. It has not been possible thus far to determine precise positions of glycan attachment to the protein backbone for many glycoproteins. This is due, in part, to the difficulties of addressing these questions experimentally because mucins and mucin-like glycoproteins are often insensitive to protease digestion and glycans are often clustered in arrays, making sequence analysis difficult (Piller and Piller, 1993; Gooley et al, 1994). Consensus motifs for glycosylation have been described for prediction of several types of glycosylation sites other than mucin-type O-glycosylation. The best characterised example is that of N-linked glycosylation of asparagine where the consensus sequence for the acceptor site has been resolved to a short peptide sequence Asn-Xaa-Ser/Thr (where Xaa cannot be Pro) (Marshall, 1972), although Asn-Xaa-Cys has also been found to be utilized. Recent studies indicate that Asn-Xaa-Ser is less well utilized compared to the Thr containing sequon (Kasturi et al, 1995). Studies of other types of glycopeptide linkages also suggest the existence of rather specific primary peptide sequences associated with glycosylation. Thus, proteoglycantype glycosylation of serine is restricted to -Ser-Gly-Xaa-Gly(Bourdon et al, 1987), and collagen-type glycosylation of hydroxylysine restricted to -Gly-Xaa-Hyl-Gly(Prockop et al., 1979). The GlcNAc-type glycosylation of serine or threonine appears to be adjacent to an acidic amino acid and within two residues of a proline (Haltiwanger et al., 1992). The Fuc-type glycosylation of serine/threonine seems to be restricted to the peptide sequence -Gly-Gly-Thr/Ser-Cys(Harris and Spellman, 1993), and recently a prokaryotic O-linked glycan type was found associated with -Asp-Ser(Plummer et al., 1995).