Concerted regulation of inhibitory activity of α1-antitrypsin by the native strain distributed throughout the molecule
Concerted regulation of inhibitory activity of α1-antitrypsin by the native strain distributed throughout the molecule
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DOI：
10.1074/jbc.m110272200
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发表时间：
2002-04-19
影响因子：
4.8
通讯作者：
Yu, MH
中科院分区：
文献类型：
--
作者：
Seo, EJ;Lee, C;Yu, MH
常见球状蛋白的天然形式处于最稳定的状态，但血浆丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）的天然形式表现出高能态相互作用。 α(1)-抗胰蛋白酶（丝氨酸蛋白酶抑制剂的原型）的高能态应变分布在整个分子中，但直接调节功能的应变似乎位于与目标蛋白酶形成复合物期间插入反应位点环的区域。为了检查该菌株在 α(1)-抗胰蛋白酶其他区域的功能作用，我们通过组合各种不单独影响活性的稳定单氨基酸取代，大大提高了分子的稳定性。结果表明，稳定性大幅提高（超过 13 kcal mol(-1)）会影响抑制活性，每 kcal mol(-1) 活性损失 11%。将影响环插入区域中的单个残基取代的活性添加到这些非常稳定的取代中导致活性进一步降低。结果表明，分布在整个分子中的天然α(1)-抗胰蛋白酶菌株以协调一致的方式调节抑制功能。
The native forms of common globular proteins are in their most stable state but the native forms of plasma serpins (serine protease inhibitors) show high energy state interactions. The high energy state strain of alpha(1)-antitrypsin, a prototype serpin, is distributed throughout the whole molecule, but the strain that regulates the function directly appears to be localized in the region where the reactive site loop is inserted during complex formation with a target protease. To examine the functional role of the strain at other regions of alpha(1)-antitrypsin, we increased the stability of the molecule greatly via combining various stabilizing single amino acid substitutions that did not affect the activity individually. The results showed that a substantial increase of stability, over 13 kcal mol(-1), affected the inhibitory activity with a correlation of 11% activity loss per kcal mol(-1). Addition of an activity affecting single residue substitution in the loop insertion region to these very stable substitutions caused a further activity decrease. The results suggest that the native strain of alpha(1)-antitrypsin distributed throughout the molecule regulates the inhibitory function in a concerted manner.