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首页> 外文期刊>Journal of Molecular Biology >Kinetic instability of the serpin Z alpha1-antitrypsin promotes aggregation.
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Kinetic instability of the serpin Z alpha1-antitrypsin promotes aggregation.

机译：丝氨酸蛋白酶抑制剂Z alpha1-抗胰蛋白酶的动力学不稳定促进聚集。

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摘要

The serpinopathies encompass a large number of diseases caused by inappropriate conformational change and self-association (polymerization) of a serpin (serine proteinase inhibitor) molecule. The most common serpinopathy is alpha(1)-antitrypsin (alpha(1)AT) deficiency, which is associated with an increased risk for liver cirrhosis, hepatocellular carcinoma and early-onset emphysema. The Z variant of alpha(1)AT, which accounts for 95% of all cases of alpha(1)AT deficiency, polymerizes during synthesis and after secretion. Here, we show using intrinsic and extrinsic fluorescence probes that Z alpha(1)AT exists in a non-native conformation. We examined the thermodynamic stability by transverse urea gradient gel electrophoresis, thermal denaturation and equilibrium guanidine hydrochloride unfolding and found that, despite structural differences between the two proteins, wild-type alpha(1)AT and Z alpha(1)AT display similar unfolding pathways and thermodynamic stabilities. Far-UV circular dichroism and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid, dipotassium salt) fluorescence suggest that the intermediate ensembles formed during unfolding of wild-type alpha(1)AT and Z alpha(1)AT are characterized by similar structural features. Kinetic analysis of the unfolding transition showed that Z alpha(1)AT unfolds at least 1.5-fold faster than the wild type. The biological implications of these data are discussed.
机译：丝瓜病包括由不适当的构象变化和丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）分子的自缔合（聚合）引起的多种疾病。最常见的脊髓病是α（1）-抗胰蛋白酶（α（1）AT）缺乏症，与肝硬化，肝细胞癌和早发性肺气肿的风险增加有关。 α（1）AT的Z变体占所有alpha（1）AT缺乏症的95％，在合成过程中和分泌后发生聚合。在这里，我们显示使用内在和外在的荧光探针，Z alpha（1）AT以非天然的构象存在。我们通过横向尿素梯度凝胶电泳，热变性和平衡胍盐酸盐展开法研究了热力学稳定性，发现，尽管两种蛋白质之间存在结构差异，野生型α（1）AT和Z alpha（1）AT仍显示相似的展开途径和热力学稳定性。远紫外线圆二色性和bis-ANS（4,4'-dianilino-1,1'-联萘-5,5'-二磺酸，双钾盐）荧光表明在野生型α（ 1）AT和Z alpha（1）AT具有相似的结构特征。展开过渡的动力学分析表明，Z alpha（1）AT的展开速度至少比野生型快1.5倍。讨论了这些数据的生物学意义。

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