STRUCTURE-FUNCTION STUDIES ON SELECTIN CARBOHYDRATE LIGANDS - MODIFICATIONS TO FUCOSE, SIALIC-ACID AND SULFATE AS A SIALIC-ACID REPLACEMENT

The selectins are a family of carbohydrate-binding proteins that have been implicated in the initial interaction between leukocytes and the vascular endothelium. The three members of this family will bind to th e sialyl-Lewis(x) epitope [Sia alpha 2-3 Gal beta 1-4 (Fuc alpha 1-3) GlcNAc] and related oligosaccharides. In this report, we examine the m olecular details of that recognition using synthesized carbohydrates w ith specific modifications on the sialyl-Lewis(x) epitope. E- and L-Se lectin require hydroxyl groups at the 2, 3 and 4 positions of the fuco se residue. P-Selectin, however, requires only the 3-position hydroxyl group, while tolerating removal of the oxygen at positions 2 or 4 of fucose residue. Modifications of the glycerol side chain or the N-acet yl group of the sialic acid have little effect an the binding of any o f the selectins. All three selectins bind efficiently to an oligosacch aride with a sulphate replacement for the sialic acid [sulpho-Lewis(x) , or SO4-3Gal beta 1-4 (Fuc alpha 1-3) Glc-ceramide]. For E-Selectin, binding to sulpho-Lewis(x) appears to be equivalent to binding to sial yl-Lewis(x), while for L- and P-Selectin binding to the sulphated stru cture shows characteristics distinct from sialyl-Lewis(x) recognition. Taken together, these data indicate that, while all three selectins c an recognize sialyl-Lewis(x), E-, L- and P-Selectin each display disti nct carbohydrate ligand preferences.