The tetrameric protein transthyretin dissociates to a non-native monomer in solution - A novel model for amyloidogenesis
The tetrameric protein transthyretin dissociates to a non-native monomer in solution - A novel model for amyloidogenesis
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DOI：
10.1074/jbc.274.46.32943
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发表时间：
1999-11-12
影响因子：
4.8
通讯作者：
Brito, RMM
中科院分区：
文献类型：
--
作者：
Quintas, A;Saraiva, MJM;Brito, RMM
在淀粉样变性中，通常无害的可溶性蛋白聚合形成不可溶的纤维，淀粉样纤维的形成和沉积与一系列疾病有关，包括海绵状脑病、阿尔茨海默病和家族性淀粉样多发性神经病(FAP)。在某些形式的FAP中，淀粉样纤维主要由转甲状腺蛋白(TTR)的变体组成，TTR是一种与甲状腺激素和视黄醇运输有关的同质四聚体蛋白，最常见的淀粉样致TTR变异体是V30M-TTR型，L55P-TTR型是与最具侵袭性的FAP相关的变异体。最近，我们报道了TTR在pH 7.0和近生理强度(Quintas，A，A，Quintas，A，Retinol，Quintas，A，A，Quintas，A，Retinol，Quintas，A，Retinol，Quintas，A，Quintas，A，Retinol，QuintasSaraiva，M，J，和Brito，R，M，(1997)es peLett，418,297-300)。在这里，我们证明了四聚体的解离显然是不可逆的；基于本征的色氨酸荧光和荧光猝灭实验，我们证明了四聚体解离形成的单体物种是非天然的。我们还表明，基于1-苯胺基-8-对苯二甲酸的结合研究，这种单体物种的行为似乎不像熔融的球体，这些数据使我们能够提出一个基于通常观察到的生理溶液条件下自然发生的四聚体解离的TTR淀粉样蛋白发生模型。
In amyloidosis, normally innocuous soluble proteins polymerize to form insoluble fibrils, Amyloid fibril formation and deposition have been associated with a wide range of diseases, including spongiform encephalopathies, Alzheimer's disease, and familial amyloid polyneuropathies (FAP), In certain forms of FAP, the amyloid fibrils are mostly constituted by variants of transthyretin (TTR), a homotetrameric plasma protein implicated in the transport of thyroxine and retinol, The most common amyloidogenic TTR variant is V30M-TTR, and L55P-TTR is the variant associated with the most aggressive form of FAP, Recently, we reported that TTR dissociates to a monomeric species at pH 7.0 and nearly physiological ionic strengths (Quintas, A, Saraiva, M, J,, and Brito, R, M, (1997) PEES Lett, 418, 297-300). Here, we show that the tetramer dissociation is apparently irreversible; and based on intrinsic tryptophan fluorescence and fluorescence quenching experiments, we show that the monomeric species formed upon tetramer dissociation is non-native. We also show, based on 1-anilino-8-naph-thalenesulfonate binding studies, that this monomeric species appears not to behave like a molten globule, These data allowed us to propose a model for TTR amyloidogenesis based on tetramer dissociation occurring naturally under commonly observed physiological solution conditions.