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.

引起肌萎缩侧索硬化症 (ALS) 的突变通常会影响 RNA 结合蛋白 (RBP) 的凝聚特性。然而，RBP 凝聚在蛋白质-RNA 复合物的特异性和功能中的作用仍不清楚。我们创建了一系列 TDP-43 C 末端结构域 (CTD) 变体，这些变体表现出从低到高的冷凝倾向梯度，如在体外和通过核迁移率和病灶形成所观察到的。值得注意的是，在 RNA 结合区域的子集上进行有效的 TDP-43 组装需要缩合能力，这些区域包含异常长的特征类型和密度的基序簇。这些“结合区域缩合物”是由同源 CTD 驱动的相互作用促进的，是有效调节结合转录本子集所必需的，包括TDP-43 mRNA。我们确定 RBP 凝聚可以以特定结合区域的方式发生，以选择性地调节转录组范围的 RNA 调控，这对在信号传导、疾病和进化的背景下重塑 RNA 网络具有重要意义。