Serotransferrin glycans

Serotransferrin glycans are generally non-fucosylated except in human cerebrospinal fluid (trace amounts) [246,247], rat (20-30% of the molecules) [221], pig (100% of the molecules) [220] and the serotransferrin-like glycoprotein from mouse milk [218,219] in which this protein co-exists with a lactotransferrin. None of the serotransferrin glycans... 

The only sialie acid found to date in serotransferrin glycans is A-acetylneuraminic acid, except in horse serotransferrin glycans which contain 4-0-acetyl, A-acetylneuraminic acid in addition to A-acetylneuraminic acid (Fig. 9) and in mouse serotransferrin in which only A-glycolylneuraminic acid is present (Fig. 7). 

Serotransferrin glycans are highly sensitive to numerous pathological modifications of protein glycosylation. For this reason, serotransferrin is used as a tool to probe changes in A-glycosylation in pathological situations, particularly in liver diseases (for reviews, see refs. [242,255,256]). 

Liver diseases. By applying the crossed affino-electrophoresis method, Spik et al. [255,256] have demonstrated that the human serotransferrin glycans are profoundly modified in liver diseases such as viral hepatitis and alcoholic cirrhosis with a marked increase of triantennary glycans (see also refs. [257-259]). 

Fig. 21. Molecular modelling (A,B) of rabbit serotransferrin glycan and (C) of human lactotransferrin [192, 210,275] (A) 3D structure of rabbit serotransferrin (B) interaction of rabbit serotransferrin glycan in a broken-wing conformation with a peptide segment (amino acids 254 to 271) in an a-helix conformation, 7,7, Al-acetylneuraminic acid residues (see Fig. 6A). (C) 3D structure of human lactotransferrin. Arrows indicate the position of glycans.

Important variations of the plasma serotransferrin concentration are observed in physiological and pathological situations. They are often accompanied by dramatic modifications of glycan primary structure (see section 3.2). 

Serotransferrins. All known serotransferrins contain one or two glycans of the A-acetyllactosaminic type which are located in the C-terminal lobe of the polypeptide chain. Hen [102], rabbit [103,104], pig [105] and rat [67] serotransferrins contain a single glycan located in a very similar position which does not correspond to Asn-413 in human serotransferrin (Fig. 2). 

Potential glycosylation sites are present in fishlWS], tobacco hornworm[Ti] and insects [72] serotransferrins, but the position of glycans in their peptide chain has not yet been determined. 

Figure 2 synthesizes the present data concerning the location of glycans on the peptide chain of different serotransferrins. It is remarkable that, except for melanotransferrin, all of the glycans or potential glycosylation sites are located in the C-domain and in very conserved positions. 

Ouotransferrins. The peptide chain of hen ovotransferrin is identical to that of hen serotransferrin. However, both glycoproteins differ only by the structure of their glycans (see Figs. 16B,D). Two potential glycosylation sites have been identified... 

Fig. 6. Primary structure of serotransferrin diantennary glycans from human (A,B) [211-213], cow (A,B) [119, 214], rabbit (A) [103], sheep (A) [119,215], marsupial (kangaroo, opossum, wallaby) (A) [119,216], Primary structure of human serotransferrin triantennary glycans (C,D) [119-217],...

Fig. 7. Primary structure of the glycans from mouse serotransferrin [119,218,219],...

Fig. 8. Primary structures of the glycans from rat serotransferrin (A,B,C)[221] and from rat mammary gland transferrin (D) [67]. R, GlcNAc(pl-4)[Fuc(al-6)]o- GlcNAc(P-N)Asn.

Fig. 9. Primary structure of the four glycans identified in the three horse serotransferrin variants [113,114,119, 222,223], R, GlcNAc(Pl-4)GlcNAc(pi-N)Asn.

Fig, )0. Primary structure of glycans from fish serotransferrins. A, Carp big-head (Aristichthys nobilis) [224] B, pike Esox lucius)[225]. R, GlcNAc(pl-4)GlcNAc(pl-N)Asn. 

Fig. 16. Primary structure of glycans from turkey ovotransferrin (A) [119,238], hen ovotransferrin (B) [239, 240], chicken embryo serum (C), and chicken serotransferrin (D)[241]. R, GlcNAc(Pl-4)GlcNAc(Pl-N)Asn. Glycans of transferrin from embryo hepatocytes secreted into culture medium are a-l,6-fucosylated.

Human seminal transferrin. Human seminal transferrin (MM 80kDa) contains 6.1% sugars. The primary structure of the major N-linked glycan is identical to that of the serotransferrin diantennary glycan of Fig. 6A [247]. 

Fig. 18. Primary structure of tetra- and pentaantennary glycans from human serotransferrin secreted into culture medium of human hepatocarcinoma cell line Hep G2. The a-l,3-linked fucose residue is conjugated to the GlcNAc of one of the antennae [261]. R, GlcNAc(pi )[Fuc(al-6)]o iGlcNAc(p-N)Asn.

CDG-type II syndrome [265,268] is a separate variant since it is characterized by a severe decrease in the activity of A-acetylglucosaminyltransferase II (UDP-GlcNAc a6-D-mannoside (3-l,2-A-acetylglucosaminyltransferase). As a consequence, the serotransferrin isoforms contain two truncated monoantennary glycans of which the primary structures are described in Fig. 19. 

Fig. 19. Primary structure of the glycan from human serotransferrin isolated from a patient with carbohydrate-deficient syndrome (CDG) type II [265,268], R, GIcNAc(pi-4)GIcNAc(pi-N)Asn.

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