Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
J Thromb Haemost. 2011 Jul;9 Suppl 1:26-34. doi: 10.1111/j.1538-7836.2011.04360.x.
Serpins have been studied as a distinct protein superfamily since the early 80s. In spite of the poor sequence homology between family members, serpins share a highly conserved core structure that is critical for their functioning as serine protease inhibitors. Therefore, discoveries made about one serpin can be related to the others. In this short review, I introduce the serpin structure and general mechanism of protease inhibition, and illustrate, using recent crystallographic and biochemical data on antithrombin (AT), how serpin activity can be modulated by cofactors. The ability of the serpins to undergo conformational change is critical for their function, but it also renders them uniquely susceptible to mutations that perturb their folding, leading to deficiency and disease. A recent crystal structure of an AT dimer revealed that serpins can participate in large-scale domain-swaps to form stable polymers, and that such a mechanism may explain the accumulation of misfolded serpins within secretory cells. Serpins play important roles in haemostasis and fibrinolysis, and although each will have some elements specifically tailored for its individual function, the mechanisms described here provide a general conceptual framework.
自 80 年代初以来，丝氨酸蛋白酶抑制剂（Serpins）一直作为一个独特的蛋白质超家族进行研究。尽管家族成员之间的序列同源性较差，但丝氨酸蛋白酶抑制剂具有高度保守的核心结构，这对于它们作为丝氨酸蛋白酶抑制剂的功能至关重要。因此，对一种丝氨酸蛋白酶抑制剂的发现可以与其他丝氨酸蛋白酶抑制剂相关。在这篇简短的综述中，我介绍了丝氨酸蛋白酶抑制剂的结构和蛋白酶抑制的一般机制，并利用最近关于抗凝血酶（AT）的晶体学和生物化学数据来说明辅因子如何调节丝氨酸蛋白酶抑制剂的活性。丝氨酸蛋白酶抑制剂构象变化的能力对于其功能至关重要，但这也使它们容易受到突变的影响，从而导致其折叠异常，引发缺陷和疾病。最近的一个 AT 二聚体晶体结构揭示了丝氨酸蛋白酶抑制剂可以参与大规模的结构域交换，形成稳定的聚合物，并且这种机制可能解释了错误折叠的丝氨酸蛋白酶抑制剂在分泌细胞内的积累。丝氨酸蛋白酶抑制剂在止血和纤维蛋白溶解中发挥着重要作用，尽管每种丝氨酸蛋白酶抑制剂都有一些针对其特定功能的特定元素，但这里描述的机制提供了一个通用的概念框架。
