Lomas D A, Finch J T, Seyama K, Nukiwa T, Carrell R W
Department of Haematology, University of Cambridge, United Kingdom.
J Biol Chem. 1993 Jul 25;268(21):15333-5.
Antitrypsin Siiyama is a rare example of the deficiency variants of antitrypsin that accumulate in the endoplasmic reticulum of the hepatocyte. The common example is Z antitrypsin, which has a mutation (Glu342-->Lys) at the junction of the head of the fifth strand of the A sheet and the base of the reactive center loop. It was previously shown that Z antitrypsin spontaneously polymerizes due to the insertion of the reactive center loop of one molecule into the A sheet of a second. The mutation in antitrypsin Siiyama (Ser53-->Phe) affects a residue that provides a ridge for the sliding movement that opens the A sheet, and it had been predicted that this would result in the same type of loop-sheet polymerization observed with the Z variant. We confirm this here and show that virtually all the plasma antitrypsin in a homozygote for the Siiyama variant was polymerized due to non-covalent bonding with a loss of accessibility of the reactive center loop. The common basis of the polymerization of Z and Siiyama antitrypsin is supported by identical findings on electron microscopy. Taken together these results confirm that loop-sheet polymerization is a general mechanism and as such is likely to be responsible for the intracellular inclusions associated with liver pathology.
抗胰蛋白酶石山型是抗胰蛋白酶缺陷变体的一个罕见例子，它会在肝细胞的内质网中积累。常见的例子是Z抗胰蛋白酶，它在A片层第五链头部与反应中心环基部的交界处有一个突变（Glu342→Lys）。先前的研究表明，Z抗胰蛋白酶会自发聚合，原因是一个分子的反应中心环插入到另一个分子的A片层中。抗胰蛋白酶石山型中的突变（Ser53→Phe）影响了一个为打开A片层的滑动运动提供脊状结构的残基，据预测这会导致与Z变体中观察到的相同类型的环-片层聚合。我们在此证实了这一点，并表明石山型变体纯合子中的几乎所有血浆抗胰蛋白酶都因非共价结合而聚合，导致反应中心环的可及性丧失。电子显微镜下的相同发现支持了Z抗胰蛋白酶和石山型抗胰蛋白酶聚合的共同基础。综合这些结果证实，环-片层聚合是一种普遍机制，因此可能是与肝脏病理相关的细胞内包涵体的成因。
