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首页> 外文期刊>Biochemistry >The Folding and Aggregation Energy Landscapes of Tethered RRM Domains of Human TDP-43 Are Coupled via a Metastable Molten Globule-like Oligomer
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The Folding and Aggregation Energy Landscapes of Tethered RRM Domains of Human TDP-43 Are Coupled via a Metastable Molten Globule-like Oligomer

机译：人TDP-43的系束性RRM结构域的折叠和聚集能量景观通过亚稳熔母状的低聚物偶联

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摘要

Stress-induced misfolding and intraneuronal aggregation of the highly conserved nucleic acid binding protein TDP-43 (transactive response DNA binding protein 43 kDa) and its fragments have been implicated in amyotrophic lateral sclerosis and several other neurodegenerative diseases. However, the physicochemical mechanism of its misfolding from the functional folded state is poorly understood. TDP-43 is a four-domain protein and performs the essential nucleic acid binding function with the help of its two tandem RNA recognition motif domains naturally tethered by a linker (called here the tethered RRM domain of TDP-43 or TDP-43(tRRM)). Here, we show that the monomeric native form of TDP-43(tRRM) remains in a pH-dependent and reversible thermodynamic equilibrium with a protonated, nanosized, 40-merit form (the A form). Under the stress-like low-pH condition, the A form becomes predominantly populated. In the A form, protein molecules have restricted dynamics of surface side-chain residues but native-like secondary structure. This self-assembled form possesses a loosely packed core in which the intrinsically disordered and aggregation-prone regions are in the proximity. The A form is metastable and swiftly aggregates into a highly stable amyloid-like protofibrillar form (beta form) mediated by the disorder-to-order transition of intrinsically disordered regions upon small environmental perturbations. Interestingly, the A form and the beta form are not formed when TDP-43(tRRM) is bound to DNA, indicating that the nucleic acid binding regions of the protein participate in their formation. Our results reveal how the energy landscapes of folding and aggregation of TDP-43(tRRM) are coupled by a metastable molten-globule like oligomeric form and modulated by stress-like conditions.
机译：应激诱导的高度保守核酸结合蛋白TDP-43（横向响应DNA结合蛋白43kDA）及其片段的肾脏诱导的误折叠和腹腔内聚集在肌萎缩的侧面硬化和几种其他神经变性疾病中涉及其片段。然而，从功能折叠状态下误折叠的物理化学机制是较差的理解。 TDP-43是四结构域蛋白质，并在其两种串联RNA识别基序结构域通过接头（此处称为TDP-43或TDP-43的系丝RRM结构域（TRRM ）））。这里，我们表明，TDP-43（Trrm）的单体天然形式保持在pH依赖性和可逆的热力学平衡中，其具有质子化，纳米型，40-优异形式（A形）。在应激状的低pH条件下，形成填充形式。在一种形式中，蛋白质分子具有表面侧链残基的限制性，但是天然的二级结构。这种自组装形式具有松散填充的核心，其中本质上无序和聚集 - 易发的区域在接近。将一种形式含量稳定，并将其迅速聚集成被在小环境扰动小的内部无序区域的无序转变介导的高度稳定的淀粉样原子纤维形式（β形式）。有趣的是，当TDP-43（TRRM）与DNA结合时，不形成形式和β形成，表明蛋白质的核酸结合区域参与其形成。我们的结果揭示了TDP-43（TRRM）的折叠和聚集的能量景观如何通过钼形式等亚稳熔融球结合，并通过应变条件调节。

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  • 来源
    《Biochemistry》 |2019年第6期|共13页
  • 作者

    Pillai Meenakshi; Jha Santosh Kumar;

  • 作者单位

    CSIR Natl Chem Lab AcSIR Phys &

    Mat Chem Div Dr Homi Bhabha Rd Pune 411008 Maharashtra India;

    CSIR Natl Chem Lab AcSIR Phys &

    Mat Chem Div Dr Homi Bhabha Rd Pune 411008 Maharashtra India;

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  • 正文语种 eng
  • 中图分类 生物化学;
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