Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
EMBO Rep. 2011 Sep 30;12(10):1011-7. doi: 10.1038/embor.2011.171.
α(1)-Antitrypsin (α1AT) deficiency is a disease with multiple manifestations, including cirrhosis and emphysema, caused by the accumulation of stable polymers of mutant protein in the endoplasmic reticulum of hepatocytes. However, the molecular basis of misfolding and polymerization remain unknown. We produced and crystallized a trimeric form of α1AT that is recognized by an antibody specific for the pathological polymer. Unexpectedly, this structure reveals a polymeric linkage mediated by domain swapping the carboxy-terminal 34 residues. Disulphide-trapping and antibody-binding studies further demonstrate that runaway C-terminal domain swapping, rather than the s4A/s5A domain swap previously proposed, underlies polymerization of the common Z-mutant of α1AT in vivo.
α(1)-抗胰蛋白酶（α1AT）缺乏症是一种具有多种表现形式的疾病，包括肝硬化和肺气肿，其病因是突变蛋白的稳定聚合物在肝细胞的内质网中积累。然而，错误折叠和聚合的分子基础仍不清楚。我们制备并结晶了一种三聚体形式的 α1AT，该蛋白可被一种针对病理聚合物的抗体识别。出乎意料的是，这种结构揭示了一种通过羧基末端 34 个残基的结构域交换介导的聚合连接。二硫键捕获和抗体结合研究进一步表明，在体内，常见的 α1AT Z 突变体的聚合是由失控的 C 端结构域交换引起的，而不是之前提出的 s4A/s5A 结构域交换。
