Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA.
UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Struct Mol Biol. 2018 Apr;25(4):311-319. doi: 10.1038/s41594-018-0045-5. Epub 2018 Mar 12.
Proteins in the fibrous amyloid state are a major hallmark of neurodegenerative disease. Understanding the multiple conformations, or polymorphs, of amyloid proteins at the molecular level is a challenge of amyloid research. Here, we detail the wide range of polymorphs formed by a segment of human TAR DNA-binding protein 43 (TDP-43) as a model for the polymorphic capabilities of pathological amyloid aggregation. Using X-ray diffraction, microelectron diffraction (MicroED) and single-particle cryo-EM, we show that the DLIIKGISVHI segment from the second RNA-recognition motif (RRM2) forms an array of amyloid polymorphs. These associations include seven distinct interfaces displaying five different symmetry classes of steric zippers. Additionally, we find that this segment can adopt three different backbone conformations that contribute to its polymorphic capabilities. The polymorphic nature of this segment illustrates at the molecular level how amyloid proteins can form diverse fibril structures.
纤维状淀粉样蛋白状态下的蛋白质是神经退行性疾病的主要标志。在分子水平上理解淀粉样蛋白的多种构象或多态性是淀粉样蛋白研究的一个挑战。在这里，我们详细描述了人类 TAR DNA 结合蛋白 43（TDP-43）的一段作为病理性淀粉样聚集多态性能力模型形成的广泛的多态性。使用 X 射线衍射、微电子衍射（MicroED）和单颗粒冷冻电镜，我们表明来自第二个 RNA 识别基序（RRM2）的 DLIIKGISVHI 片段形成淀粉样多态性的排列。这些缔合包括七个不同的界面，显示五个不同的空间拉链对称类。此外，我们发现该片段可以采用三种不同的骨架构象，这有助于其多态性能力。该片段的多态性性质在分子水平上说明了淀粉样蛋白如何能够形成不同的纤维结构。
