A phenylalanine 402 to leucine mutation is responsible for a stable inactive conformation of antithrombin.
In a South African family with antithrombin deficiency and unexplained thrombosis, genomic DNA analysis revealed a substitution of Phe 402 by Leu. This mutation involves an amino acid located in the carboxyterminal side of the antithrombin reactive loop and has already been observed in a French family (antithrombin Maisons-Laffitte). In both cases, the expression of the mutation is pleiotropic, i.e. results in a reduction in the circulating concentration of antithrombin and impairs both its anti-thrombin activity and its ability to bind heparin. The effect of a denaturing agent (sodium dodecyl sulfate) on the recognition of the plasma antithrombin by a polyclonal antibody was studied in an immuno-enzymatic assay. The Phe to Leu mutation decreased the sensitivity to denaturation, suggesting that the mutation increases the stability of the protein. Whether this stable conformation is due to a partial insertion of the amino-terminal side of the reactive loop, which would explain how both protease binding and heparin binding are affected, remains to be determined.
Emmerich
J
J
CJF INSERM 91-01, Groupe de Recherche sur la Thrombose, Université Paris V, France.
Chadeuf
G
G
Coetzee
M J
MJ
Alhenc-Gelas
M
M
Fiessinger
J N
JN
Aiach
M
M
D000293:Adolescent; D000328:Adult; D000991:Antithrombins / Q000737:chemistry* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007930:Leucine / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010649:Phenylalanine / Q000235:genetics*; D011487:Protein Conformation
D000991:Antithrombins; D010649:Phenylalanine; D007930:Leucine