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首页> 外文期刊>Biochemistry >Role of the Glutamic Acid 54 Residue in Transthyretin Stability and Thyroxine Binding
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Role of the Glutamic Acid 54 Residue in Transthyretin Stability and Thyroxine Binding

机译：谷氨酸54残基在运甲状腺素蛋白稳定性和甲状腺素结合中的作用

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Transthyretin (TTR) is a tetrameric protein associated with amyloidosis caused by tetramerndissociation andmonomermisfolding. The structure of two TTRvariants (E54Gand E54K)withGlu54 pointnmutation that cause clinically aggressive amyloidosis remains unclear, although amyloidogenicity of artificialntriple mutations (residues 53-55) in β-strand D had been investigated. Here we first analyzed the crystalnstructures and biochemical and biophysical properties of E54G and E54K TTRs. The direction of the Lys15nside chain in E54K TTR and the surface electrostatic potential in the edge region in both variants werendifferent from those of wild-type TTR. The presence of Lys54 leads to destabilization of tetramer structurendue to enhanced electrostatic repulsion between Lys15 of two monomers. Consistent with structural data, thenbiochemical analyses demonstrated that E54G and E54K TTRs were more unstable than wild-type TTR.nFurthermore, the entrance of the thyroxine (T4) binding pocket in TTRwasmarkedly narrower in E54KTTRnand wider in E54G TTR compared with wild-type TTR. The tetramer stabilization and amyloid fibrilnformation assays in the presence of T4 showed lower tetramer stability andmore fibril formation in E54KandnE54G TTRs than in wild-type TTR, suggesting decreased T4 binding to the TTR variants. These findingsnindicate that structural modification by Glu54 point mutation may sufficiently alter tetramer stability andnT4 binding
机译：运甲状腺素蛋白（TTR）是一种四聚体蛋白，与四聚体结合和单体折叠引起的淀粉样变性有关。尽管已经研究了β-链D中人工三联体突变（残基53-55）的淀粉样变性，但两个具有Glu54点突变的TTR变体（E54G和E54K）的结构仍不清楚。在这里，我们首先分析了E54G和E54K TTR的晶体结构以及生化和生物物理特性。在两个变体中，E54K TTR中Lys15nside链的方向和边缘区域的表面静电势与野生型TTR相同。 Lys54的存在导致四聚体结构的不稳定，这归因于两个单体的Lys15之间增强的静电排斥。与结构数据一致，然后生化分析表明E54G和E54K TTR比野生型TTR更不稳定.n此外，与野生型TTR相比，TTR中的甲状腺素（T4）结合口袋的入口在E54KTTRn中明显更窄，在E54G TTR中更宽。在存在T4的情况下，四聚体稳定性和淀粉样蛋白原纤维形成试验显示，与野生型TTR相比，E54KandnE54G TTR中的四聚体稳定性更低，原纤维形成更多，表明T4与TTR变异体的结合降低。这些发现表明，通过Glu54点突变进行的结构修饰可以充分改变四聚体稳定性和nT4结合。

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