C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease
C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease
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DOI：
10.1074/jbc.m700841200
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发表时间：
2007-07-20
影响因子：
4.8
通讯作者：
Zavodszky, Peter
中科院分区：
文献类型：
--
作者：
Beinrohr, Laszlo;Harmat, Veronika;Zavodszky, Peter
C1 抑制剂是丝氨酸蛋白酶抑制剂家族的成员，是血液中炎症过程的主要下调剂。 C1 抑制剂的遗传缺陷会导致遗传性血管性水肿，这是一种显性遗传的、可能致命的疾病。在这里，我们报告了人类 C1 抑制剂丝氨酸蛋白酶抑制剂结构域的第一个晶体结构，代表了以前未报道的潜在形式，它解释了几种自然发生的突变的功能后果，其中两个突变被详细讨论。所呈现的结构显示出具有七链β-折叠A的新颖构象。C端六个残基的独特构象表明其在活性-潜在转变中作为屏障的潜在作用。根据表面电荷模式、肝素亲和力测量和肝素二糖的对接，在丝氨酸蛋白酶抑制剂-蛋白酶相遇复合物的接触区域中提出了肝素结合位点。我们展示了聚阴离子如何通过新颖的“三明治”机制改变 C1 抑制剂的活性，解释了早期的反应动力学和诱变研究。这些结果可能有助于改进用于治疗遗传性血管水肿、器官移植排斥和心脏病的治疗性 C1 抑制剂制剂。
C1 inhibitor, a member of the serpin family, is a major down-regulator of inflammatory processes in blood. Genetic deficiency of C1 inhibitor results in hereditary angioedema, a dominantly inheritable, potentially lethal disease. Here we report the first crystal structure of the serpin domain of human C1 inhibitor, representing a previously unreported latent form, which explains functional consequences of several naturally occurring mutations, two of which are discussed in detail. The presented structure displays a novel conformation with a seven-stranded beta-sheet A. The unique conformation of the C-terminal six residues suggests its potential role as a barrier in the active-latent transition. On the basis of surface charge pattern, heparin affinity measurements, and docking of a heparin disaccharide, a heparin binding site is proposed in the contact area of the serpin-proteinase encounter complex. We show how polyanions change the activity of the C1 inhibitor by a novel "sandwich" mechanism, explaining earlier reaction kinetic and mutagenesis studies. These results may help to improve therapeutic C1 inhibitor preparations used in the treatment of hereditary angioedema, organ transplant rejection, and heart attack.