title: Proposed heparin binding site in antithrombin based on arginine 47. A new variant Rouen-II, 47 Arg to Ser.
abstract: Antithrombin Rouen-II, a new inherited variant of antithrombin-III, was found in two members of a family with no definite history of thrombosis. The subjects had normal antigenic concentrations of antithrombin and normal progressive inhibitory activity. However, the variant had defective heparin and heparan sulfate cofactor activities, and was not activated by a synthetic pentasaccharide representing the minimum heparin sequence. The abnormal antithrombin was isolated using heparin-Sepharose chromatography, and on electrophoresis at pH 8.6 migrated more anodally than normal. Two-dimensional peptide mapping of tryptic and Staphylococcus aureus V8 protease digests was performed and the abnormal peptide was located by tryptophan staining. Amino acid sequence studies demonstrated a substitution of arginine at residue 47 by a serine. Evidence strongly suggests that arginine 47 is a prime heparin binding site in antithrombin and that it forms part of a proposed positively charged linear site (to which heparin binds) that stretches across the surface of the molecule from the A to the D helix.
authors.affiliation: Laboratoire d'Hémostase, Centre Hospitalier Universitaire Rouen, France.
authors.forename: J Y
authors.initials: JY
authors.lastname: Borg
authors.forename: M C
authors.initials: MC
authors.lastname: Owen
authors.forename: C
authors.initials: C
authors.lastname: Soria
authors.forename: J
authors.initials: J
authors.lastname: Soria
authors.forename: J
authors.initials: J
authors.lastname: Caen
authors.forename: R W
authors.initials: RW
authors.lastname: Carrell
mesh_terms: D000328:Adult; D000991:Antithrombins / Q000235:genetics / Q000378:metabolism*; D001120:Arginine; D001665:Binding Sites; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D013329:Structure-Activity Relationship
chemical_list: D000991:Antithrombins; D006493:Heparin; D001120:Arginine