Structure-function studies on selectin carbohydrate ligands. Modifications to fucose, sialic acid and sulphate 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 the sialyl-Lewisx epitope [Sia alpha 2-3 Gal beta 1-4 (Fuc alpha 1-3) GlcNAc] and related oligosaccharides. In this report, we examine the molecular details of that recognition using synthesized carbohydrates with specific modifications on the sialyl-Lewisx epitope. E- and L-Selectin require hydroxyl groups at the 2, 3 and 4 positions of the fucose 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-acetyl group of the sialic acid have little effect on the binding of any of the selectins. All three selectins bind efficiently to an oligosaccharide with a sulphate replacement for the sialic acid [sulpho-Lewisx, or SO4-3Gal beta 1-4 (Fuc alpha 1-3) Glc-ceramide]. For E-Selectin, binding to sulpho-Lewisx appears to be equivalent to binding to sialyl-Lewisx, while for L- and P-Selectin binding to the sulphated structure shows characteristics distinct from sialyl-Lewisx recognition. Taken together, these data indicate that, while all three selectins can recognize sialyl-Lewisx, E-, L- and P-Selectin each display distinct carbohydrate ligand preferences.
Brandley
B K
BK
Glycomed, Inc., Alameda, CA 94501.
Kiso
M
M
Abbas
S
S
Nikrad
P
P
Srivasatava
O
O
Foxall
C
C
Oda
Y
Y
Hasegawa
A
A
D050260:Carbohydrate Metabolism; D002240:Carbohydrate Sequence; D002241:Carbohydrates / Q000737:chemistry; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D019040:E-Selectin; D005643:Fucose / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019041:L-Selectin; D016256:Lewis X Antigen / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D012794:Sialic Acids / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry / Q000378:metabolism*
D002241:Carbohydrates; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D016256:Lewis X Antigen; D008024:Ligands; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D012794:Sialic Acids; D013431:Sulfates; D019041:L-Selectin; D005643:Fucose; D019158:N-Acetylneuraminic Acid