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首页> 外文期刊>Journal of Molecular Biology >Protein subunit interactions and structural integrity of amyloidogenic transthyretins: Evidence from electrospray mass spectrometry
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Protein subunit interactions and structural integrity of amyloidogenic transthyretins: Evidence from electrospray mass spectrometry

机译：淀粉样蛋白运甲状腺素蛋白的蛋白质亚基相互作用和结构完整性：电喷雾质谱的证据

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Wild-type and variant transthyretins form amyloid fibrils in two different diseases. The biologically active form of transthyretin is a tetramer but there is evidence that a monomeric species is the amyloidogenic intermediate. Using mass spectrometry we have developed an approach to monitor the proportions of monomer and tetramer in wild-type and variant transthyretins, and found a strong correlation between the instability of the tetramer in the gas phase and the amyloidogenicity of the protein variant. The presence of water molecules in the central channel has been found to be critical for maintaining intact the complex in the gas phase, with additional stability observed in the presence of excess thyroxine. The solution structure of monomeric transthyretin under fibril-forming conditions was studied using hydrogen exchange monitored by mass spectrometry. The results show that Val30Met transthyretin, the commonest amyloidogenic variant, exhibits loss of hydrogen exchange protection substantially more rapidly than the wild-type protein, suggesting partial unfolding of the beta-sheet structure. These results provide new insights into the correlation between tetramer stability and amyloidogenicity as well as supporting a possible route to fibril formation via transient unfolding of the transthyretin monomer. (C) 1998 Academic Press. [References: 36]
机译：野生型和变型甲状腺素蛋白在两种不同的疾病中形成淀粉样原纤维。运甲状腺素蛋白的生物活性形式是四聚体，但有证据表明单体是淀粉样蛋白生成中间体。使用质谱技术，我们开发了一种方法来监测野生型和变体甲状腺素蛋白中单体和四聚体的比例，并发现气相中四聚体的不稳定性与蛋白质变体的淀粉样变性之间存在很强的相关性。已经发现中央通道中水分子的存在对于保持气相中的复合物完整至关重要，在过量的甲状腺素存在下观察到额外的稳定性。使用通过质谱监测的氢交换研究了在原纤维形成条件下单体运甲状腺素蛋白的溶液结构。结果显示，Val30Met转甲状腺素蛋白是最常见的淀粉样蛋白生成变体，与野生型蛋白相比，其失去氢交换保护的速度要快得多，这表明β-折叠结构的部分展开。这些结果为四聚体稳定性和淀粉样变性之间的相关性提供了新的见解，并支持通过运甲状腺素蛋白单体的瞬时展开来形成原纤维的可能途径。 （C）1998年学术出版社。 [参考：36]

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