A unique trisaccharide sequence in heparin mediates the early step of antithrombin III activation.
Spectrofluorimetry experiments using synthetic trisaccharides indicate that in compounds that display affinity for antithrombin III (AT-III), a unique trisaccharide sequence plays the key role in the early recognition, and the first step of AT-III activation. Added to previous observations, these new results suggest that the two-step binding mechanism previously proposed (Olson et al., J. Biol. Chem., 1981, 256, 11073-11079) might involve, in the first place, a conformational change of the protein, induced by the trisasaccharide -->4)-O-(6-O-sulfo-2-sulfoamino-2-deoxy-alpha-D-glucopyranosyl)-(1 -->4)- O-(beta-D-glucopyranosyluronic acid)-(1-->4)-O-(3,6-di-O-sulfo-2-sulfoamino-2- deoxy-alpha-D-glucopyranosyl)-(1-->, then would follow the fitting which ends in the locked complex. These observations support the new paradigm invoking specific oligosaccharide sequences in selective interactions of glycosaminoglycans and proteins.
Petitou
M
M
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Barzu
T
T
Herault
J P
JP
Herbert
J M
JM
D000990:Antithrombin III / Q000378:metabolism*; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D009844:Oligosaccharides; D000990:Antithrombin III; D006493:Heparin