...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Biochemistry >Structure-Based Mutagenesis Reveals Critical Residues in the Transferrin Receptor Participating in the Mechanism of pH-Induced Release of Iron from Human Serum Transferrin
【24h】

Structure-Based Mutagenesis Reveals Critical Residues in the Transferrin Receptor Participating in the Mechanism of pH-Induced Release of Iron from Human Serum Transferrin

机译：基于结构的诱变揭示了转铁蛋白受体中的关键残基，参与人血清转铁蛋白的pH诱导的铁释放机制。

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

The recent crystal structure of two monoferric human serum transferrin (FeNhTF) molecules bound to the soluble portion of the homodimeric transferrin receptor (sTFR) has provided new details about this binding interaction that dictates the delivery of iron to cells. Specifically, substantial rearrangements in the homodimer interface of the sTFR occur as a result of the binding of the two FeNhTF molecules. Mutagenesis of selected residues in the sTFR highlighted in the structure was undertaken to evaluate the effect on function. Elimination of Ca~(2+) binding in the sTFR by mutating two of four coordinating residues ([E465A,E468A]) results in low production of an unstable and aggregated sTFR. Mutagenesis of two histidines ([H475A,H684A]) at the dimer interface had little effect on the kinetics of release of iron at pH 5.6 from either lobe, reflecting the inaccessibility of this cluster to solvent. Creation of an H318A sTFR mutant allows assignment of a small pH-dependent initial decrease in the magnitude of the fluorescence signal to His318. Removal of the four C-terminal residues of the sTFR, Asp757-Asn758- Glu759-Phe760, eliminates pH-stimulated release of iron from the C-lobe of the Fe_2hTF/sTFR Δ757-760 complex. The inability of this sTFR mutant to bind and stabilize protonated hTF His349 (a pH-inducible switch) in the C-lobe of hTF accounts for the loss. Collectively, these studies support a model in which a series of pH-induced events involving both TFR residue His318 and hTF residue His349 occurs to promote receptor-stimulated release of iron from the C-lobe of hTF.
机译：与同型二聚体转铁蛋白受体（sTFR）的可溶性部分结合的两个单铁人血清转铁蛋白（FeNhTF）分子的最新晶体结构提供了有关这种结合相互作用的新细节，该相互作用决定了铁向细胞的传递。具体而言，由于两个FeNhTF分子的结合，sTFR的同源二聚体界面发生了明显的重排。对结构中突出显示的sTFR中的选定残基进行诱变，以评估其对功能的影响。通过突变四个配位残基中的两个（[E465A，E468A]）来消除sTFR中的Ca〜（2+）结合，会导致不稳定和聚集的sTFR的产量降低。在二聚体界面诱变两个组氨酸（[H475A，H684A]）对pH值为5.6的铁从任一叶的释放动力学影响不大，反映出该簇难以接近溶剂。 H318A sTFR突变体的创建允许将与pH值相关的小幅度初始降低分配给His318。去除sTFR的四个C末端残基Asp757-Asn758-Glu759-Phe760，消除了pH刺激的铁从Fe_2hTF / sTFRΔ757-760复合物的C瓣释放。此sTFR突变体无法结合和稳定hTF C瓣中质子化的hTF His349（pH诱导开关），这是造成损失的原因。总体而言，这些研究支持一个模型，其中发生一系列涉及TFR残基His318和hTF残基His349的pH诱导事件，以促进受体刺激的铁从hTF的C瓣释放。

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