Instituto de Química Física Rocasolano (IQFR), CSIC, E-28006, Madrid, Spain.
Centro de Biología Molecular "Severo Ochoa", Universidad Autónoma de Madrid, Cantoblanco, E-28049, Madrid, Spain.
Nat Commun. 2023 Jan 28;14(1):466. doi: 10.1038/s41467-023-36023-z.
The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43´s prion-like domain. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1δ. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease.
RNA 结合蛋白 TDP-43 通过其 C 端类似朊病毒的结构域在几种神经退行性疾病中形成细胞质包含体。在尚未明确的结构转换下，TDP-43 发生相分离并从液相转变为固相，这种转换由氧化应激和伴侣蛋白抑制引发。尽管分子伴侣对蛋白质聚集病理具有明确的保护作用，但对疾病相关朊病毒中伴侣蛋白识别的决定因素知之甚少。在这里，我们表明伴侣蛋白和共伴侣蛋白主要识别 TDP-43 类似朊病毒结构域的结构元件。重要的是，虽然 HSP70 和 HSP90 伴侣蛋白促进 TDP-43 相分离，但来自人类 HSP40 家族三个类别的共伴侣蛋白（即 DNAJA2、DNAJB1、DNAJB4 和 DNAJC7）对 TDP-43 去混合的影响明显不同。TDP-43 类似朊病毒结构域中第二个螺旋元件的蛋氨酸亚砜化破坏相分离和淀粉样形成，取消伴侣蛋白识别并改变酪蛋白激酶-1δ的磷酸化。我们的结果表明，翻译后修饰的 TDP-43 类似朊病毒结构域的变态编码了决定因素，这些决定因素控制着疾病中具有重要意义的机制。
