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首页> 外文期刊>Biochemistry >Conformational Dynamics of Metal-Binding Domains in Wilson Disease Protein: Molecular Insights into Selective Copper Transfer
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Conformational Dynamics of Metal-Binding Domains in Wilson Disease Protein: Molecular Insights into Selective Copper Transfer

机译：威尔逊病蛋白中金属结合域的构象动力学：选择性铜转移的分子见解。

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摘要

ATP7A/B are human P1B-typeATPases involved in cellular Cu homeostasis. TheN-terminal partsnof these multidomain proteins contain six metal-binding domains (MBDs) connected by linkers. The MBDsnare similar in structure to each other and to the human copper chaperone Atox1, although their distinct rolesnin Cu transfer appear to vary. All domains have the ferredoxin-like fold and a solvent-exposed loop with anMXCXXC motif that can bind CuIn. Here, we investigated the dynamic behavior of the individual MBDsn(WD1-WD6) in ATP7B in apo forms using molecular dynamic simulations.We also performed simulationsnof three Cu-bound forms (WD2c, WD4c, and WD6c). Our results reveal molecular features that varyndistinctly among the MBDs. Whereas WD1, WD2, and WD6 have well-defined Cu loop conformationsnstabilized by a network of interactions,WD4 andWD5 exhibit greater loop flexibility and, inWD4, helix R1nunwinds and rewinds. WD3, which has the lowest sequence identity, behaves differently and its Cu loop isnrigid with respect to the rest of the domain. Cu coordination reduces structural dynamics in all domains butnWD4c. In agreement with predictions on individual domains, simulations of the six possible Atox1-WDnheterocomplexes show that Atox1 interactions with WD4 are the strongest. This study provides molecularnexplanations for reported Cu transfer and protein-protein interaction specificity
机译：ATP7A / B是人类P1B型ATP酶，参与细胞Cu稳态。这些多结构域蛋白的N末端部分包含通过接头连接的六个金属结合结构域（MBD）。 MBDsnare的结构彼此相似，与人类铜伴侣蛋白Atox1相似，尽管它们在Cu转移中的独特作用似乎有所不同。所有结构域均具有类似铁氧还蛋白的折叠和带有可与CuIn结合的MXCXXC基序的溶剂暴露环。在这里，我们使用分子动力学模拟研究了apo形式的单个MBDsn（WD1-WD6）在ATP7B中的动力学行为，还对三种Cu结合形式（WD2c，WD4c和WD6c）进行了模拟。我们的研究结果揭示了MBD之间分子特征的差异。 WD1，WD2和WD6具有定义明确的Cu环构象，并通过相互作用网络稳定化，而WD4和WD5则显示出更大的环灵活性，而在WD4中，螺旋R1则不缠绕和倒带。具有最低序列同一性的WD3行为不同，并且其Cu环相对于其余结构域而言是刚性的。 Cu配位可降低butnWD4c所有域的结构动力学。与对单个域的预测一致，对六种可能的Atox1-WDnheterocomplexes的仿真显示，Atox1与WD4的相互作用最强。这项研究为报道的铜转移和蛋白质-蛋白质相互作用特异性提供了分子解释

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  • 来源
    《Biochemistry》 |2009年第25期|p.5849-5863|共15页
  • 作者

    Agustina Rodriguez-Granillo Alejandro Crespo and Pernilla Wittung-Stafshede;

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    ‡Department of Biochemistry and Cell Biology, Rice University, Houston, 77251 Texas,§Department of Bioengineering, RiceUniversity, Houston, 77005 Texas, and ) Department of Chemistry, Umea University, 901 87 Umea, Sweden †Funds were provided bythe Robert A. Welch Foundation (C-1588) and the Swedish Research Council (2008-2947). Partial supportcomes fromRiceComputationalResearchCluster (NSFCNS-0421109), the SharedUniversityGrid atRice (NSFEIA-0216467), and from a partnership between Rice University, Sun Microsystems, and Sigma Solutions, Inc.;

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