THE MECHANISM OF Z-ALPHA-1-ANTITRYPSIN ACCUMULATION IN THE LIVER
THE MECHANISM OF Z-ALPHA-1-ANTITRYPSIN ACCUMULATION IN THE LIVER
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DOI：
10.1038/357605a0
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发表时间：
1992-06-18
期刊：
影响因子：
64.8
通讯作者：
CARRELL, RW
中科院分区：
文献类型：
--
作者：
LOMAS, DA;EVANS, DL;CARRELL, RW
大多数北方欧洲人只有血浆蛋白酶抑制剂α-1-抗胰蛋白酶的正常M型，但约4%的人是Z缺乏变体1的杂合子。由于尚未充分理解的原因，Z突变导致肝2中抗胰蛋白酶加工的最后阶段的阻断，使得在Z纯合子中仅15%的蛋白质被分泌到血浆中，未分泌的85%的α-1-抗胰蛋白酶积累在肝细胞的内质网中;其大部分被降解，但剩余部分聚集形成不溶性细胞内内含物。这些夹杂物与肝细胞损伤有关，10%的新生儿Z纯合子发展为肝病，这通常导致致命的儿童肝硬化。在这里，我们展示了这种积累的分子病理学基础，并描述了抗胰蛋白酶中的Z突变如何导致一个分子的反应中心环和另一个A-片层中的差距之间的独特分子相互作用。Z抗胰蛋白酶的这种环-片聚合在37 ℃下自发发生，并通过将特定肽插入抗胰蛋白酶分子的A-片层中而完全阻断。体外聚合的Z抗胰蛋白酶具有与Z纯合子肝细胞分离的包涵体相同的性质和超微结构。这种环片聚合的浓度和温度依赖性对新生儿Z纯合子的肝脏疾病的管理具有影响。
MOST northern Europeans have only the normal M form of the plasma protease inhibitor alpha-1-antitrypsin, but some 4% are heterozygotes for the Z deficiency variant 1. For reasons that have not been well-understood, the Z mutation results in a blockage in the final stage of processing of antitrypsin in the liver 2 such that in the Z homozygote only 15% of the protein is secreted into the plasma.The 85% of the alpha-1-antitrypsin that is not secreted accumulates in the endoplasmic reticulum of the hepatocyte; much of it is degraded but the remainder aggregates to form insoluble intracellular inclusions. These inclusions are associated with hepatocellular damage, and 10% of newborn Z homozygotes develop liver disease which often leads to a fatal childhood cirrhosis. Here we demonstrate the molecular pathology underlying this accumulation and describe how the Z mutation in antitrypsin results in a unique molecular interaction between the reactive centre loop of one molecule and the gap in the A-sheet of another. This loop-sheet polymerization of Z antitrypsin occurs spontaneously at 37-degrees-C and is completely blocked by the insertion of a specific peptide into the A-sheet of the antitrypsin molecule. Z antitrypsin polymerized in vitro has identical properties and ultrastructure to the inclusions isolated from hepatocytes of a Z homozygote. The concentration and temperature dependence of this loop-sheet polymerization has implications for the management of the liver disease of the newborn Z homozygote.