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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cα-trace model of the transmembrane domain of human copper transporter 1, motion and functional implications
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Cα-trace model of the transmembrane domain of human copper transporter 1, motion and functional implications

机译：人铜转运蛋白1跨膜结构域的Cα-迹线模型，运动和功能意义

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摘要

The trimeric human copper transporter 1 (hCTR1) is essential for copper uptake and is implicated in sensitivity to chemotherapy drugs. Using the cryoelectron microscopy (cryoEM) map of hCTR1 and evolutionary data, we constructed a Cot-trace model of the membrane region. The model structure, supported by mutagenesis data, was used to investigate global dynamics through elastic network models. Identified as dominant hinge regions, hCTRVs MxxxM and GxxxG motifs were shown to have significant roles in functional movements characterized by the two slowest modes of motion. Both modes predicted significant changes at the wide cytoplasmic pore region; the slowest mode introduced a rotational motion around the pore central axis, whereas in the following mode the cytoplasmic parts of the helices approached and moved away from the pore center. In the most cooperative mode, the MxxxM motif in the extracellular narrow region remained static. The second mode of motion, however, predicted a cooperative rotational motion of this copper-binding motif, possibly reflecting activation at the pore's extracellular entrance. We suggest a molecular mechanism of copper transport in which this motif serves both as a gate and as a selectivity filter. We also suggest residues that are responsible for pH activation.
机译：三聚体人类铜转运蛋白1（hCTR1）对铜的摄取至关重要，并且涉及对化疗药物的敏感性。使用hCTR1的低温电子显微镜（cryoEM）图和进化数据，我们构建了膜区域的Cot迹线模型。诱变数据支持的模型结构用于通过弹性网络模型研究全局动力学。被鉴定为主要的铰链区，hCTRV MxxxM和GxxxG基序显示出在以两种最慢运动模式为特征的功能性运动中具有重要作用。两种模式都预测在宽的细胞质孔区域会发生显着变化。最慢的模式导致围绕孔中心轴的旋转运动，而在随后的模式中，螺旋的胞质部分接近并远离孔中心。在最合作的模式下，细胞外狭窄区域中的MxxxM基序保持静态。然而，第二种运动模式预测了这种铜结合基序的协同旋转运动，可能反映了孔的细胞外入口处的激活。我们提出了铜运输的分子机制，其中该基序既充当门，又充当选择性过滤器。我们还建议残留物负责pH活化。

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  • 作者

    Maya Schushan; rnYariv Barkan; rnTurkan Haliloglu; Nir Ben-Tal;

  • 作者单位

    Department of Biochemistry and Molecular Biology, George 5. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978 Israel;

    rnDepartment of Biochemistry and Molecular Biology, George 5. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978 Israel;

    Polymer Research Center and Chemical Engineering Department, Bogazici University, Bebek 34342 Istanbul, Turkey;

    rnDepartment of Biochemistry and Molecular Biology, George 5. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978 Israel;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    dynamics; hCTRI; mechanism; model structure; structural bioinformatics;

    机译：动力学;hCTRI;机制;模型结构;结构生物信息学;

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