New aspects of siglec binding specificities, including the significance of fucosylation and of the sialyl-Tn epitope. Sialic acid-binding immunoglobulin superfamily lectins.
The siglecs (sialic acid-binding immunoglobulin superfamily lectins) are immunoglobulin superfamily members recognizing sialylated ligands. Most prior studies of siglec specificities focused on alpha2-3- and alpha2-6-sialyllactos(amin)es and on one or two of the siglecs at a time. Here, we explore several new aspects of specificities of the first six reported siglecs, using sialylated glycans presented in multivalent form, on synthetic polyacrylamide backbones, or on mucin polypeptides. First, we report that binding of siglec-1 (sialoadhesin), siglec-3 (CD33), siglec-4a (myelin-associated glycoprotein), and siglec-5 to alpha2-3 sialyllactosamine is affected markedly by the presence of an alpha1-3-linked fucose. Thus, while siglecs may not interfere with selectin-mediated recognition, fucosylation could negatively regulate siglec binding. Second, in contrast to earlier studies, we find that siglec-3 prefers alpha2-6-sialyllactose. Third, siglec-5 binds alpha2-8-linked sialic acid, making it the siglec least specific for linkage recognition. Fourth, siglecs-2 (CD22), -3, -5, and -6 (obesity-binding protein 1) showed significant binding to sialyl-Tn (Neu5Acalpha2-6-GalNAc), a tumor marker associated with poor prognosis. Fifth, siglec-6 is an exception among siglecs in not requiring the glycerol side chain of sialic acid for recognition. Sixth, all siglecs require the carboxyl group of sialic acid for binding. Finally, the presentation of the sialyl-Tn epitope and/or more extended structures that include this motif may be important for optimal recognition by the siglecs. This was concluded from studies using ovine, bovine, and porcine submaxillary mucins and Chinese hamster ovary cells transfected with ST6GalNAc-I and/or the mucin polypeptide MUC1.
Brinkman-Van der Linden
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Glycobiology Research and Training Center and Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.
Varki
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D015703:Antigens, CD / Q000378:metabolism; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D001665:Binding Sites; D002240:Carbohydrate Sequence; D000939:Epitopes / Q000276:immunology*; D005643:Fucose / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D037102:Lectins / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D011485:Protein Binding; D013237:Stereoisomerism
D015703:Antigens, CD; D015295:Antigens, Tumor-Associated, Carbohydrate; D000939:Epitopes; D007136:Immunoglobulins; D037102:Lectins; C055491:sialosyl-Tn antigen; D005643:Fucose