Molecular and functional differences induced in thrombospondin-1 by the single nucleotide polymorphism associated with the risk of premature, familial myocardial infarction.
Molecular and functional differences induced in thrombospondin-1 by the single nucleotide polymorphism associated with the risk of premature, familial myocardial infarction.
复制标题
单核苷酸多态性引起的血小板反应蛋白-1 的分子和功能差异与过早家族性心肌梗死的风险相关。
DOI：
10.1074/jbc.m311090200
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Byzova,TatianaV
中科院分区：
文献类型：
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作者：
Narizhneva,NatalyaV;Byers-Ward,VickyJ;Quinn,MartinJ;Zidar,FrankJ;Plow,EdwardF;Topol,EricJ;Byzova,TatianaV
血栓反应蛋白-1残基700处的丝氨酸（Ser-700）氨基酸而不是天冬酰胺（Asn-700）与家族性早发心脏病的风险增加有关。我们现在已经确定了Ser-700和Asn-700血栓反应蛋白-1变体之间的功能和结构差异。与Asn-700变异相比，Ser-700变异增加了血小板聚集的速度和程度，并在血小板表面表达增加。这些差异可归因于Ser-700变体与血小板表面纤维蛋白原的增强相互作用，并且与Ser-700个体的血栓形成前表型一致。Ser-700变型的血栓反应蛋白-1在构象上比Asn-700变型更不稳定，这表现在对蛋白水解消化的易感性增加和对变性剂展开的易感性增加。这些数据提示了与早发性心肌梗死相关的遗传风险因素的潜在分子和细胞基础。
A serine (Ser-700) amino acid rather than an asparagine (Asn-700) at residue 700 of thrombospondin-1 has been linked to an increased risk for development of premature, familial heart attacks. We now have identified both functional and structural differences between the Ser-700 and Asn-700 thrombospondin-1 variants. The Ser-700 variant increased the rate and extent of platelet aggregation and showed increased surface expression on platelets compared with the Asn-700 variant. These differences could be ascribed to an enhanced interaction of the Ser-700 variant with fibrinogen on the platelet surface and are consistent with a prothrombotic phenotype in Ser-700 individuals. The Ser-700 variant thrombospondin-1 was conformationally more labile than the Asn-700 variant as demonstrated by increased susceptibility to proteolytic digestion and enhanced susceptibility to unfolding by denaturants. These data suggest a potential molecular and cellular basis for a genetic risk factor associated with early onset myocardial infarction.