Stability and crystal structures of His88 mutant human transthyretins
Stability and crystal structures of His88 mutant human transthyretins
复制标题
DOI：
10.1002/1873-3468.12704
复制
发表时间：
2017-07
期刊：
影响因子：
3.5
通讯作者：
T. Yokoyama;Yuma Hanawa;T. Obita;M. Mizuguchi
中科院分区：
文献类型：
--
作者：
T. Yokoyama;Yuma Hanawa;T. Obita;M. Mizuguchi
人转甲状腺素蛋白 (TTR) 的不稳定与其错误折叠和聚集有关。之前对 TTR 中子晶体结构的研究表明，H88 周围包含水分子的大型氢键网络与野生型 TTR (WT-TTR) 的稳定性有显着关系。在这里，我们证明与 WT-TTR 相比，与淀粉样心肌病相关的 H88R 突变体显着不稳定。为了阐明H88和氢键网络在TTR稳定性中的作用，我们确定了H88突变体（H88A、H88F、H88Y和H88S）的热力学稳定性和晶体结构。我们的结果表明，在某些情况下，由于结合水分子的变化以及 TTR 本身的结构变化，TTR 不稳定。
Destabilization of human transthyretin (TTR) has been implicated in its misfolding and aggregation. A previous study on the neutron crystal structure of TTR suggested that a large hydrogen bond network around H88 which includes water molecules is significantly involved in the stability of wild‐type TTR (WT‐TTR). Here, we demonstrate that the H88R mutant associated with amyloid cardiomyopathy is substantially destabilized compared with WT‐TTR. In order to clarify the role of H88 and the hydrogen bond network in the stability of TTR, we determined the thermodynamic stability and the crystal structure of H88 mutants (H88A, H88F, H88Y, and H88S). Our results suggest that in some cases TTR is destabilized due to alterations in bound water molecules as well as structural changes in TTR itself.