• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated {Delta}E-torsinA mutant.
【24h】

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated {Delta}E-torsinA mutant.

机译：躯干A对膜蛋白的作用揭示了与肌张力障碍相关的{E} -torsinA突变体的功能丧失和显性负表型。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Most cases of early-onset torsion dystonia (EOTD) are caused by a deletion of one glutamic acid in the carboxyl terminus of a protein named torsinA. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wild-type protein. Although there is increasing evidence that dysfunction of the dopamine system is implicated in the development of EOTD, the biological function of torsinA and its relation to dopaminergic neurotransmission has remained unexplored. Here, we show that torsinA can regulate the cellular trafficking of the dopamine transporter, as well as other polytopic membrane-bound proteins, including G protein-coupled receptors, transporters, and ion channels. This effect was prevented by mutating the ATP-binding site in torsinA. The dystonia-associated torsinA deletion mutant (DeltaE-torsinA) did not have any effect on the cell surface distribution of polytopic membrane-associated proteins, suggesting that the mutation linked with EOTD results in a loss of function. However, a mutation in the ATP-binding site in DeltaE-torsinA reversed the aggregate phenotype associated with the mutant. Moreover, the deletion mutant acts as a dominant-negative of wild-type torsinA through a mechanism presumably involving association of wild-type and mutant torsinA. Taken together, our results provide evidence for a functional role for torsinA and a loss of function and a dominant-negative phenotype of the DeltaE-torsinA mutation. These properties may contribute to the autosomal dominant nature of the condition.
机译：多数早期扭转性肌张力障碍（EOTD）病例是由称为torsinA的蛋白质的羧基末端缺失一个谷氨酸引起的。与野生型蛋白质的内质网定位相反，该突变导致蛋白质聚集在核周内含物中。尽管越来越多的证据表明多巴胺系统功能异常与EOTD的发展有关，但都没有研究torsinA的生物学功能及其与多巴胺能神经传递的关系。在这里，我们证明了TorsinA可以调节多巴胺转运蛋白以及其他多位膜结合蛋白的细胞运输，包括G蛋白偶联受体，转运蛋白和离子通道。通过突变TorsinA中的ATP结合位点可以防止此作用。与肌张力障碍相关的TorsinA缺失突变体（DeltaE-torsinA）对多膜相关蛋白的细胞表面分布没有任何影响，这表明与EOTD相关的突变导致功能丧失。但是，DeltaE-torsinA中ATP结合位点的突变逆转了与该突变体相关的总表型。此外，缺失突变体通过推测与野生型和突变体torsinA缔合的机理而成为野生型torsinA的显性负性。两者合计，我们的结果提供了TorsinA的功能作用和DeltaE-torsinA突变的功能丧失和显性负表型的证据。这些性质可能有助于该病的常染色体显性遗传。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号