• 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 >Disease-associated mutant α-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity
【24h】

Disease-associated mutant α-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity

机译：疾病相关突变体α-actinin-4揭示了一种调节其F-肌动蛋白结合亲和力的机制

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

α-Actinin-4 is a widely expressed protein that employs an act in-binding site with two calponin homology domains to crosslink actin filaments (F-actin) in a Ca~(2+)-sensitive manner in vitro. An inherited, late-onset form of kidney failure is caused by point mutations in the α-actinin-4 actin-binding domain. Here we show that α-actinin-4/F-actin aggregates, observed in vivo in podocytes of humans and mice with disease, likely form as a direct result of the increased actin-binding affinity of the protein. We document that exposure of a buried actin-binding site 1 in mutant α-actinin-4 causes an increase in its actin-binding affinity, abolishes its Ca~(2+) regulation in vitro, and diverts its normal localization from actin stress fibers and focal adhesions in vivo. Inactivation of this buried actin-binding site returns the affinity of the mutant to that of the WT protein and abolishes aggregate formation in cells. In vitro, actin filaments crosslinked by the mutant α-actinin-4 exhibit profound changes of structural and biomechanical properties compared with WT α-actinin-4. On a molecular level, our findings elucidate the physiological importance of a dynamic interaction of α-actinin with F-actin in podocytes in vivo. We propose that a conformational change with full exposure of actin-binding site 1 could function as a switch mechanism to regulate the actin-binding affinity of α-actinin and possibly other calponin homology domain proteins under physiological conditions.
机译：α-Actinin-4是一种广泛表达的蛋白，它利用带有两个钙蛋白同源域的act结合位点在体外以Ca〜（2+）敏感的方式交联肌动蛋白丝（F-actin）。遗传性肾功能衰竭的晚期发作是由α-actinin-4肌动蛋白结合域中的点突变引起的。在这里，我们显示在人和患有疾病的小鼠的足细胞中在体内观察到的α-肌动蛋白-4 / F-肌动蛋白聚集体可能是由于该蛋白的肌动蛋白结合亲和力增加的直接结果。我们记录了突变的α-actinin-4中埋藏的肌动蛋白结合位点1的暴露导致其肌动蛋白结合亲和力的增加，在体外取消了其Ca〜（2+）调节，并从肌动蛋白应激纤维转移了其正常定位和体内粘连。该埋藏的肌动蛋白结合位点的失活使突变体与WT蛋白的亲和力恢复，并消除了细胞中的聚集体形成。在体外，与WTα-actinin-4相比，与突变型α-actinin-4交联的肌动蛋白丝表现出深刻的结构和生物力学性能变化。在分子水平上，我们的发现阐明了体内足细胞中α-肌动蛋白与F-肌动蛋白的动态相互作用的生理重要性。我们提出构象变化与肌动蛋白结合位点1的充分暴露可以作为一个开关机制，以调节生理条件下α-肌动蛋白和其他钙还原蛋白同源域蛋白的肌动蛋白结合亲和力。

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