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首页> 外文期刊>International journal of molecular medicine >VLHL plasminogen activator inhibitor spontaneously reactivates from the latent to active form.
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VLHL plasminogen activator inhibitor spontaneously reactivates from the latent to active form.

机译：VLHL纤溶酶原激活剂抑制剂自发地从潜在形式重新活化为活性形式。

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摘要

Wild-type plasminogen activator inhibitor type 1 (PAI-1) is a fast-acting uPA and tPA inhibitor with half-life of 1-2 h. Recombinant PAI-1 with two mutations, Q197C and G355C, shows a very long half-life (VLHL). An introduced disulfide bridge holds together two central, parallel strands of beta-sheet A, preventing their separation to incorporate residues P4-P14 during the serpin's transition into latency. An active PAI-1 is usually described as a single structure with the reactive center loop (RCL) with P1-P1' (R369-M370) extended far from the bulk of the serpin's body. We have found that VLHL PAI-1 exists in several active forms that travel with different electrophoretic mobilities. Under aerobic conditions, two distinct active forms are observed. Upon reduction of cysteines, the VLHL mutant converts into the latent form, which spontaneously reactivates into a fully or partially active serpin, with yet another mobility. Utilizing electrophoresis, zymography (to check PAI-1 activity toward uPA) and theoretical calculations for molecular modeling, we have characterized active 1, 2, 3 and latent conformers of VLHL PAI-1 and their behaviors at normal and elevated temperatures, and in normal or reducing environments. VLHL PAI-1 activity is not affected, and the molecules do not polymerize unless reduced and/or heated. VLHL PAI-1 associates into dimers and bigger oligomers when -SH groups become available for oxidation and formation of intra- or intermolecular -S-S- bridges between conformers of different shapes and activities. We postulate that the active structures differ in RCL conformation and their position in relation to the gate region and the rest of the molecule.
机译：野生型纤溶酶原激活物抑制剂1型（PAI-1）是速效uPA和tPA抑制剂，半衰期为1-2小时。具有两个突变Q197C和G355C的重组PAI-1显示了非常长的半衰期（VLHL）。引入的二硫键将β-sheetA的两条平行的中央链连接在一起，从而防止它们在Serpin转变为潜伏期时分离并结合残基P4-P14。有源PAI-1通常被描述为具有反应性中心回路（RCL）的单个结构，其中P1-P1'（R369-M370）延伸得远远超出丝氨酸蛋白酶抑制剂的主体。我们发现VLHL PAI-1以几种活性形式存在，并以不同的电泳迁移率传播。在有氧条件下，观察到两种不同的活性形式。半胱氨酸还原后，VLHL突变体转化为潜伏形式，自发激活为完全或部分活性的丝氨酸蛋白酶抑制剂，并具有另一种迁移能力。利用电泳，酶谱分析（检查PAI-1对uPA的活性）和分子建模的理论计算，我们表征了VLHL PAI-1的活性1、2、3和潜在构象异构体，以及它们在常温和高温以及正常情况下的行为或减少环境。 VLHL PAI-1活性不受影响，除非还原和/或加热，否则分子不会聚合。当-SH基团可用于氧化和形成不同形状和活性的构象异构体之间的分子内或分子间-S-S-桥时，VLHL PAI-1缔合成二聚体和更大的低聚物。我们假设活性结构的RCL构象及其相对于门区域和分子其余部分的位置不同。

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