• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Human mutation >Substrate interaction defects in histidyl‐tRNA synthetase linked to dominant axonal peripheral neuropathy
【24h】

Substrate interaction defects in histidyl‐tRNA synthetase linked to dominant axonal peripheral neuropathy

机译：与显性轴突周围神经病变有关的组氨基 - TRNA合成酶中的底物相互作用缺陷

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

Abstract Histidyl‐tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcot‐Marie‐Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog ( HTS1 ). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2W‐linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wild‐type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMT‐associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology.
机译：摘要组氨基-TRNA合成酶（HARS）将组氨酸连接到同源的TRNA分子，这是蛋白质翻译所必需的。哈尔斯的突变导致主导的轴突外周神经病变Charcot-Marie-Dootty疾病2W（CMT2W）;然而，精确的分子机制仍未确定。在这里，我们研究了三个与CMT2W相关的突发突变（p.tyr330cys，p.ser356aSn和p.val155gly）。将三个突变定位于HARS催化结构域，未被补充缺失酵母直脑（HTS1）。使用酶动力学，差示扫描荧光测定法（DSF）和分析超速离心（AUC）来评估这些取代对原发性氨基酰化功能和整体二聚体结构的影响。值得注意的是，P.Tyr330Cys，P.Ser356ASN和P.Val155Gly串联替换所有导致氨基酰化降低，在CMT2W连接的HARS突变和规范ARS损失之间提供直接连接。虽然DSF测定显示，相对于野生型，只有一种变体（P.Val155gly）的热稳定性，但所有三个突变体都形成了稳定的二聚体，如AUC所测量。我们的作品代表了CMT相关的HARS突变的第一种生化分析，并强调了原发性氨基酰化功能的损失如何有助于病理病理。

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