Inactive conformation of the serpin α1-antichymotrypsin indicates two-stage insertion of the reactive loop:: Implications for inhibitory function and conformational disease
Inactive conformation of the serpin α1-antichymotrypsin indicates two-stage insertion of the reactive loop:: Implications for inhibitory function and conformational disease
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DOI：
10.1073/pnas.97.1.67
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发表时间：
2000-01-04
影响因子：
11.1
通讯作者：
Lomas, DA
中科院分区：
文献类型：
--
作者：
Gooptu, B;Hazes, B;Lomas, DA
丝氨酸蛋白酶抑制剂是蛋白酶抑制剂家族，在蛋白水解级联反应的控制中发挥核心作用。它们的抑制机制取决于反应环在被靶蛋白酶切割后分子内插入到β折叠A中。蛋白质内的点突变可以允许异常构象转变，其特征在于一个分子的反应环和另一个分子的β折叠A之间的β链交换。这些环片聚合物导致各种疾病，如肝硬化，肺气肿，血管性水肿和血栓形成，我们最近已经表明，它们是早发性痴呆的基础，我们在这里报告的生化特性和晶体结构的血浆丝氨酸蛋白酶抑制剂α（1）-抗胰凝乳蛋白酶作为一个非活性中间体捕获的天然存在的变体（Leu-55-Pro）。该结构显示了丝氨酸蛋白酶抑制剂构型，反应性环部分插入β-折叠A中。片层的下部由F-螺旋的最后一圈和将其连接到s3 A的环填充，这种构象与丝氨酸蛋白酶抑制剂中复合物和聚合物形成途径上的拟议中间体的构象相匹配，特别是，这种中间体，沿着潜在的和聚合的构象，解释了与Leu-55-Pro突变患者的慢性阻塞性肺疾病相关的血浆α（1）-抗糜蛋白酶活性丧失。
The serpins are a family of proteinase inhibitors that play a central role in the control of proteolytic cascades. Their inhibitory mechanism depends on the intramolecular insertion of the reactive loop into beta-sheet A after cleavage by the target proteinase, Point mutations within the protein can allow aberrant conformational transitions characterized by beta-strand exchange between the reactive loop of one molecule and beta-sheet A of another. These loop-sheet polymers result in diseases as varied as cirrhosis, emphysema, angio-oedema, and thrombosis, and we recently have shown that they underlie an early-onset dementia, We report here the biochemical characteristics and crystal structure of a naturally occurring variant (Leu-55-Pro) of the plasma serpin alpha(1)-antichymotrypsin trapped as an inactive intermediate. The structure demonstrates a serpin configuration with partial insertion of the reactive loop into beta-sheet A. The lower part of the sheet is filled by the last turn of F-helix and the loop that links it to s3A, This conformation matches that of proposed intermediates on the pathway to complex and polymer formation in the serpins, In particular, this intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma alpha(1)-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55-Pro mutation.