Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants
Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants
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DOI：
10.1073/pnas.96.6.3108
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Lundgren, E
中科院分区：
文献类型：
--
作者：
Goldsteins, G;Persson, H;Lundgren, E
从血浆蛋白甲状腺素运载蛋白（TTR）生成淀粉样蛋白的结构要求尚不清楚，尽管假定TTR在淀粉样蛋白中部分错误折叠。在寻找对淀粉样蛋白形成重要的结构决定因素时，我们产生了具有高形成淀粉样蛋白潜力的TTR突变体。我们证明，突变体代表了一系列构象变化的中间体，导致淀粉样蛋白，两个单克隆抗体产生针对该突变体，每个显示亲和力。用于表达TTR和具有淀粉样蛋白折叠的TTR突变体，但不用于表达野生型TTR或显示野生型折叠的突变体。两个隐藏的表位在此映射到TTR的一个结构域，其中大多数与淀粉样变性相关的突变发生，并且我们提出在淀粉样蛋白形成的初始阶段被置换，打开TTR单体自聚集所需的新表面，结果为TTR的淀粉样中间体的结构变化提供了直接的生化证据。
The structural requirements for generation of amyloid from the plasma protein transthyretin (TTR) are not known, although it is assumed that TTR is partly misfolded in amyloid. In a search for structural determinants important for amyloid formation, we generated a TTR mutant with high potential to form amyloid. We demonstrated that the mutant represents an intermediate in a series of conformational changes leading to amyloid, Two monoclonal antibodies were generated against this mutant; each displayed affinity. to ex File TTR and TTR mutants with amyloidogenic folding but not to wild-type TTR or mutants exhibiting the wild-type fold. Two cryptic epitopes Here mapped to a domain of TTR where most mutations associated with amyloidosis occur and which we propose is displaced at the initial phase of amyloid formation, opening up new surfaces necessary for autoaggregation of TTR monomers, The results provide direct biochemical evidence for structural changes in an amyloidogenic intermediate of TTR.