α1-Antitrypsin polymerization and the serpinopathies:: pathobiology and prospects for therapy
α1-Antitrypsin polymerization and the serpinopathies:: pathobiology and prospects for therapy
复制标题
DOI：
10.1172/jci200216782
复制
发表时间：
2002-12-01
影响因子：
15.9
通讯作者：
Mahadeva, R
中科院分区：
文献类型：
--
作者：
Lomas, DA;Mahadeva, R
α1-抗胰蛋白酶的Z突变发生在β折叠A链5头的残基P17（靠近P1反应中心的17个残基）和移动的反应环的底部。该突变打开β折叠A，从而有利于插入第二个α1-抗胰蛋白酶分子的反应环，形成二聚体（图2）。然后，该过程可以延伸以形成在肝脏的内质网中缠结并形成包涵体的聚合物（5）。支持这一模型的证据是，纯化的Z α1-抗胰蛋白酶在生理条件下孵育时形成聚合物链（3）。该速率可以通过将温度升高至41 ℃来加速，并且可以通过引入与环竞争退火至β-折叠A的肽来阻断。在肝硬化Z α1-抗胰蛋白酶纯合子（3）的肝脏包涵体和表达Z变体的细胞系（6）中发现α1-抗胰蛋白酶聚合物，证实了体内聚合的作用。此外，阻断聚合的点突变增加了爪蟾卵母细胞表达系统中α1-抗胰蛋白酶突变体的分泌（7）。我们现在已经确定了α1-抗胰蛋白酶和丝氨酸蛋白酶抑制剂超家族的其他成员形成聚合物的以下途径（参考文献8的方程式1）：
The Z mutation of α1-antitrypsin is at residue P17 (17 residues proximal to the P1 reactive center) at the head of strand 5 of β-sheet A and the base of the mobile reactive loop. The mutation opens β-sheet A, thereby favoring the insertion of the reactive loop of a second α1-antitrypsin molecule to form a dimer (Figure 2). This process can then extend to form polymers that tangle in the endoplasmic reticulum of the liver and form inclusion bodies (5). Support for this model comes from the demonstration that purified Z α1-antitrypsin forms chains of polymers when incubated under physiological conditions (3). The rate can be accelerated by raising the temperature to 41 C and can be blocked by introducing peptides that compete with the loop for annealing to β-sheet A. The role of polymerization in vivo has been confirmed by the finding of α1-antitrypsin polymers in inclusion bodies from the liver of a Z α1-antitrypsin homozygote with cirrhosis (3) and in cell lines expressing the Z variant (6). Moreover, point mutations that block polymerization increased the secretion of mutants of α1-antitrypsin from a Xenopus oocyte expression system (7). We have now defined the following pathway by which α1-antitrypsin and other members of the serpin superfamily form polymers (equation 1 from ref. 8):