Molecular Mechanism of Z α1-Antitrypsin Deficiency.
Molecular Mechanism of Z α1-Antitrypsin Deficiency.
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Z α1-抗胰蛋白酶缺乏症的分子机制。
DOI：
10.1074/jbc.m116.727826
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发表时间：
2016-07-22
期刊：
影响因子：
--
通讯作者：
Zhou A
中科院分区：
文献类型：
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作者：
Huang X;Zheng Y;Zhang F;Wei Z;Wang Y;Carrell RW;Read RJ;Chen GQ;Zhou A
4%的北欧人携带α1-抗胰蛋白酶（α1-AT）的Z突变（E342K），由于肺中α1-AT的功能下降，易导致肺气肿的早期发作，并且由于肝细胞中聚合物的积累而导致肝硬化。然而，目前尚不清楚为什么Z突变会引起新生Z α1-AT的细胞内聚合，以及为什么15%表达的Z α1-AT作为功能性但具有聚合性的单体分泌到循环中。在这里，我们解决了z单体的晶体结构，并进行了工程替换，以评估残基Glu-342在α1-AT中的构象作用。结果表明，Z α1-AT具有中心β-片a （s5A）的不稳定链5，其晶体结构在天然抑制构象（如图所示）和异常构象（仅部分纳入中心β-片）之间达到平衡。这种由Glu-342侧链失去相互作用引起的异常构象解释了为什么Z α1-AT易于聚合并容易与6-mer肽结合，并且它支持了将5a退火到中心β-片是蛇蛋白亚稳构象形成的关键步骤。该研究表明，通过结合小分子稳定不稳定的5a可以纠正异常构象，为Z α1-AT缺乏症开辟了一种潜在的治疗方法。
The Z mutation (E342K) of α1-antitrypsin (α1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional α1-AT in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. However, it remains unclear why the Z mutation causes intracellular polymerization of nascent Z α1-AT and why 15% of the expressed Z α1-AT is secreted into circulation as functional, but polymerogenic, monomers. Here, we solve the crystal structure of the Z-monomer and have engineered replacements to assess the conformational role of residue Glu-342 in α1-AT. The results reveal that Z α1-AT has a labile strand 5 of the central β-sheet A (s5A) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5A only partially incorporated into the central β-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z α1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central β-sheet is a crucial step in the serpins' metastable conformational formation. The demonstration that the aberrant conformation can be rectified through stabilization of the labile s5A by binding of a small molecule opens a potential therapeutic approach for Z α1-AT deficiency.