Hammarström P, Schneider F, Kelly J W
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road BCC265, La Jolla, CA 92037, USA.
Science. 2001 Sep 28;293(5539):2459-62. doi: 10.1126/science.1062245.
The transthyretin (TTR) amyloid diseases, representative of numerous misfolding disorders, are of considerable interest because there are mutations that cause or suppress disease. The Val30 --> Met30 (V30M) TTR mutation is the most prevalent cause of familial amyloid polyneuropathy in heterozygotes, whereas a Thr119 --> Met119 (T119M) mutation on the second TTR allele protects V30M carriers from disease. Here, we show that the incorporation of one or more T119M TTR subunits into a predominantly V30M tetramer strongly stabilized the mixed tetramer against dissociation. Dissociation is required for amyloid formation, so these findings provide a molecular explanation for intragenic trans-suppression of amyloidosis. The data also suggest a potential therapeutic strategy, provide insight into tissue-specific deposition and amyloid composition, and support the validity of the amyloid hypothesis in human disease.
转甲状腺素蛋白（TTR）淀粉样变性疾病是众多错误折叠疾病的代表，因其存在导致或抑制疾病的突变而备受关注。Val30→Met30（V30M）TTR突变是杂合子家族性淀粉样多神经病最常见的病因，而第二个TTR等位基因上的Thr119→Met119（T119M）突变可保护V30M携带者不患该病。在此，我们表明，将一个或多个T119M TTR亚基掺入主要为V30M的四聚体中，可强烈稳定混合四聚体，防止其解离。淀粉样蛋白形成需要解离，因此这些发现为淀粉样变性的基因内反式抑制提供了分子解释。这些数据还提示了一种潜在的治疗策略，有助于深入了解组织特异性沉积和淀粉样蛋白组成，并支持淀粉样蛋白假说在人类疾病中的有效性。
