英国弗朗西斯-克里克研究所Jernej Ule、Martina Hallegger等研究人员合作发现，TDP-43的凝集特性影响其RNA结合和调节范围。相关论文于2021年8月10日在线发表在《细胞》杂志上。
研究人员创造了一系列TDP-43的C端结构域（CTD）变体，这些变体表现出从低到高的凝集倾向梯度，正如在体外和通过核流动性和灶点形成观察到的那样。值得注意的是，凝集能力是TDP-43在RNA结合区子集上有效组装所必需的，这些子集包含具有特征类型和密度的长模体簇。这些"结合区凝集物"是由同源CTD驱动的相互作用所促进的，并且是有效调节结合的转录物子集所必需的，包括TDP-43 mRNA的自动调节。
研究人员发现，RBP凝集能够以结合区特异性的方式发生，从而选择性地调节整个转录组范围的RNA调控，这对于在信号传递、疾病和进化的背景下重塑RNA网络具有意义。
据介绍，引起肌萎缩性脊髓侧索硬化症（ALS）的突变常常影响RNA结合蛋白（RBP）的凝集特性。然而，RBP凝集在蛋白质-RNA复合物的特异性和功能中的作用仍不清楚。
附：英文原文
Title: TDP-43 condensation properties specify its RNA-binding and regulatory repertoire
Author: Martina Hallegger, Anob M. Chakrabarti, Flora C.Y. Lee, Bo Lim Lee, Aram G. Amalietti, Hana M. Odeh, Katie E. Copley, Jack D. Rubien, Bede Portz, Klara Kuret, Ina Huppertz, Frédérique Rau, Rickie Patani, Nicolas L. Fawzi, James Shorter, Nicholas M. Luscombe, Jernej Ule
Issue&Volume: 2021-08-10
Abstract: Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, a capacity for condensation was required for efficient TDP-43 assembly on subsets of RNA-binding regions, which contain unusually long clusters of motifs of characteristic types and density. These “binding-region condensates” are promoted by homomeric CTD-driven interactions and required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. We establish that RBP condensation can occur in a binding-region-specific manner to selectively modulate transcriptome-wide RNA regulation, which has implications for remodeling RNA networks in the context of signaling, disease, and evolution.
DOI: 10.1016/j.cell.2021.07.018
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00877-1