Emmerich J, Chadeuf G, Coetzee M J, Alhenc-Gelas M, Fiessinger J N, Aiach M
CJF INSERM 91-01, Groupe de Recherche sur la Thrombose, Université Paris V, France.
Thromb Res. 1994 Nov 1;76(3):307-15. doi: 10.1016/0049-3848(94)90202-x.
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.
在一个患有抗凝血酶缺乏症且有不明原因血栓形成的南非家庭中，基因组DNA分析显示第402位苯丙氨酸被亮氨酸取代。这种突变涉及抗凝血酶反应环羧基末端一侧的一个氨基酸，并且已在一个法国家庭（抗凝血酶梅松拉菲特型）中观察到。在这两个案例中，该突变的表现具有多效性，即导致抗凝血酶的循环浓度降低，并损害其抗凝血酶活性及其结合肝素的能力。在免疫酶测定中研究了变性剂（十二烷基硫酸钠）对多克隆抗体识别血浆抗凝血酶的影响。苯丙氨酸到亮氨酸的突变降低了对变性的敏感性，表明该突变增加了蛋白质的稳定性。这种稳定构象是否是由于反应环氨基末端一侧的部分插入所致，这将解释蛋白酶结合和肝素结合是如何受到影响的，仍有待确定。
