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首页> 外文期刊>Journal of Molecular Biology >Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility.
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Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility.

机译：酶原向尿激酶型纤溶酶原激活剂的激活与域间柔性的增加有关。

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摘要

A key regulatory step for serine proteases of the trypsin clan is activation of the initially secreted zymogens, leading to an increase in activity by orders of magnitude. Zymogen activation occurs by cleavage of a single peptide bond near the N-terminus of the catalytic domain. Besides the catalytic domain, most serine proteases have N-terminal A-chains with independently folded domains. Little is known about how zymogen activation affects the interplay between domains. This question is investigated with urokinase-type plasminogen activator (uPA), which has an epidermal growth factor domain and a kringle domain, connected to the catalytic domain by a 15-residue linker. uPA has been implicated under several pathological conditions, and one possibility for pharmacological control is targeting the conversion of the zymogen pro-uPA to active uPA. Therefore, a small-angle X-ray scattering study of the conformations of pro-uPA and uPA in solution was performed. Structural models for the proteins were derived using available atomic-resolution structures for the various domains. Active uPA was found to be flexible with a random conformation of the amino-terminal fragment domain with respect to the serine protease domain. In contrast, pro-uPA was observed to be rigid, with the amino-terminal fragment domain in a fixed position with respect to the serine protease domain. Analytical ultracentrifugation analysis supported the observed difference between pro-uPA and uPA in overall shape and size seen with small-angle X-ray scattering. Upon association of either of two monoclonal Fab (fragment antigen-binding) fragments that are directed against the catalytic domain of, respectively, pro-uPA and uPA, rigid structures were formed.
机译：胰蛋白酶家族的丝氨酸蛋白酶的关键调节步骤是激活最初分泌的酶原，从而导致活性增加几个数量级。酶原激活是通过切割催化结构域N端附近的单个肽键而发生的。除催化结构域外，大多数丝氨酸蛋白酶均具有带有独立折叠结构域的N端A链。关于酶原激活如何影响域之间相互作用的了解甚少。使用尿激酶型纤溶酶原激活剂（uPA）来研究这个问题，它具有一个表皮生长因子结构域和一个kringle结构域，通过15个残基的连接子连接到催化结构域。 uPA已经牵涉到几种病理条件，并且药理控制的一种可能性是针对酶原pro-uPA向活性uPA的转化。因此，对溶液中pro-uPA和uPA的构象进行了小角度X射线散射研究。蛋白质的结构模型是使用各个域的可用原子拆分结构得出的。发现活性uPA具有柔性，相对于丝氨酸蛋白酶结构域具有氨基末端片段结构域的随机构象。相反，观察到前uPA是刚性的，其氨基末端片段结构域相对于丝氨酸蛋白酶结构域处于固定位置。分析超离心分析支持在小角度X射线散射中观察到的pro-uPA和uPA在总体形状和大小上的差异。当两个分别针对pro-uPA和uPA催化结构域的单克隆Fab（片段抗原结合）片段中的一个结合时，就形成了刚性结构。

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