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首页> 外文期刊>RSC Advances >T54R mutation destabilizes the dimer of superoxide dismutase 1(T54R) by inducing steric clashes at the dimer interface
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T54R mutation destabilizes the dimer of superoxide dismutase 1(T54R) by inducing steric clashes at the dimer interface

机译：T54R突变通过在二聚体界面处诱导空间冲突来稳定超氧化物歧化酶1（T54R）的二聚体

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摘要

Mutations cause abnormalities in protein structure, function and oligomerization. Different mutations in the superoxide dismutase 1 (SOD1) protein cause its misfolding, loss of dimerization and aggravate its aggregation in the amyotrophic lateral sclerosis disease. In this study, we report the mechanistic details of how a threonine-to-arginine mutation at the 54(th) position (T54R) of SOD1 results in destabilization of the dimer interface of SOD1(T54R). Using computational and experimental methods, we show that the T54R mutation increases fluctuation of the mutation-harboring loop (R54-loop) of SOD1(T54R). Fluctuation of this loop causes steric clashes that involve arginine-54 (R54) and other residues of SOD1(T54R), resulting in loss of inter-subunit contacts at the dimer interface. Since the T54 residue-containing loop is necessary for the dimerization of wild-type SOD1, fluctuation of the R54-loop, steric clashes involving R54 and loss of inter-subunit contacts give rise to the loss of SOD1(T54R) dimer stability. This correlates to energetically unfavorable tethering of the monomers of SOD1(T54R). The outcome is gradual splitting of SOD1(T54R) dimers into monomers, thereby exposing the previously buried hydrophobic interface residues to the aqueous environment. This event finally leads to aggregation of SOD1(T54R). T54R mutation has no effect in altering the relative positions of copper and zinc ion binding residues of SOD1(T54R). The native SOD1 structure is stable, and there is no destabilizing effect at its dimer interface. Overall, our study reveals the intricate mechanism of T54R mutation-associated destabilization of the dimer of the SOD1(T54R) protein.
机译：突变导致蛋白质结构，功能和低聚的异常。超氧化物歧化酶1（SOD1）蛋白中的不同突变导致其误用，二聚化丧失，并加剧了肌营养的侧面硬化疾病中的其聚集。在这项研究中，我们报告了SOD1的54（TH）位置（T54R）的苏氨酸 - 精氨酸突变如何导致SOD1（T54R）的二聚体界面的破坏性。使用计算和实验方法，我们表明T54R突变增加了SOD1（T54R）的突变窝水环（R54环）的波动。该环的波动导致涉及精氨酸-54（R54）和SOD1（T54R）的其他残留物的空间冲突，导致二聚体界面处的亚基间触点的损失。由于含有T54残基的环是野生型SOD1的二聚化所必需的，因此R54环的波动，涉及R54的空间冲突和亚基间障碍的丧失引起SOD1（T54R）二聚体稳定性的损失。这种与SOD1（T54R）的单体的能量不利的束缚相关。结果是将SOD1（T54R）二聚体的逐渐分离成单体，从而将先前掩埋的疏水性界面残留物暴露于含水环境中。此活动最终导致SOD1（T54R）的聚合。 T54R突变在改变SOD1（T54R）的铜和锌离子结合残留物的相对位置没有作用。天然的SOD1结构是稳定的，并且在其二聚体界面上没有稳定的效果。总体而言，我们的研究揭示了SOD1（T54R）蛋白二聚体的T54R突变相关稳定化的复杂机制。

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  • 来源
    《RSC Advances》 |2020年第18期|共13页
  • 作者

    Ghosh Debasish Kumar; Kumar Abhishek; Ranjan Akash;

  • 作者单位

    Ctr DNA Fingerprinting &

    Diagnost Computat &

    Funct Genom Grp Hyderabad 500039 Telangana India;

    Ctr DNA Fingerprinting &

    Diagnost Computat &

    Funct Genom Grp Hyderabad 500039 Telangana India;

    Ctr DNA Fingerprinting &

    Diagnost Computat &

    Funct Genom Grp Hyderabad 500039 Telangana India;

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  • 正文语种 eng
  • 中图分类 化学;
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