Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Sci Rep. 2019 Apr 16;9(1):6171. doi: 10.1038/s41598-019-42367-8.
Aberrant expression, dysfunction and particularly aggregation of a group of RNA-binding proteins, including TDP-43, FUS and RBM45, are associated with neurological disorders. These three disease-linked RNA-binding proteins all contain at least one RNA recognition motif (RRM). However, it is not clear if these RRMs contribute to their aggregation-prone character. Here, we compare the biophysical and fibril formation properties of five RRMs from disease-linked RNA-binding proteins and five RRMs from non-disease-associated proteins to determine if disease-linked RRMs share specific features making them prone to self-assembly. We found that most of the disease-linked RRMs exhibit reversible thermal unfolding and refolding, and have a slightly lower average thermal melting point compared to that of normal RRMs. The full domain of TDP-43 RRM1 and FUS RRM, as well as the β-peptides from these two RRMs, could self-assemble into fibril-like aggregates which are amyloids of parallel β-sheets as verified by X-ray diffraction and FT-IR spectroscopy. Our results suggest that some disease-linked RRMs indeed play important roles in amyloid formation and shed light on why RNA-binding proteins with RRMs are frequently identified in the cellular inclusions of neurodegenerative diseases.
异常表达、功能障碍，特别是一组 RNA 结合蛋白（包括 TDP-43、FUS 和 RBM45）的聚集，与神经退行性疾病有关。这三种与疾病相关的 RNA 结合蛋白都至少含有一个 RNA 识别基序（RRM）。然而，目前尚不清楚这些 RRM 是否有助于它们易于聚集的特性。在这里，我们比较了来自疾病相关 RNA 结合蛋白的五个 RRM 和来自非疾病相关蛋白的五个 RRM 的生物物理和纤维形成特性，以确定疾病相关的 RRM 是否具有使其易于自我组装的特定特征。我们发现，大多数与疾病相关的 RRM 表现出可逆的热变性和复性，并且与正常 RRM 相比，其平均热熔点略低。TDP-43 RRM1 和 FUS RRM 的完整结构域，以及来自这两个 RRM 的β-肽，可以自组装成纤维状聚集体，如 X 射线衍射和 FT-IR 光谱所证实的那样，这些聚集体是平行β-片层的淀粉样纤维。我们的结果表明，一些与疾病相关的 RRM 确实在淀粉样形成中起重要作用，并解释了为什么具有 RRM 的 RNA 结合蛋白经常在神经退行性疾病的细胞包含物中被发现。
