TDP-43 condensation properties specify its RNA-binding and regulatory repertoire.
TDP-43 condensation properties specify its RNA-binding and regulatory repertoire.
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DOI：
10.1016/j.cell.2021.07.018
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发表时间：
2021-09-02
期刊：
影响因子：
64.5
通讯作者：
Ule J
中科院分区：
文献类型：
--
作者：
Hallegger M;Chakrabarti AM;Lee FCY;Lee BL;Amalietti AG;Odeh HM;Copley KE;Rubien JD;Portz B;Kuret K;Huppertz I;Rau F;Patani R;Fawzi NL;Shorter J;Luscombe NM;Ule J
导致肌萎缩侧索硬化症（ALS）的突变通常会影响RNA结合蛋白（RBP）的缩合特性。然而，RBP缩合在蛋白质-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，其表现出从低到高的冷凝倾向梯度，如在体外以及通过核迁移率和病灶形成所观察到的。值得注意的是，一个冷凝的能力是需要有效的TDP-43组件上的RNA结合区域的子集，其中包含异常长的集群的特征类型和密度的基序。这些“结合区缩合物”由同源CTD驱动的相互作用促进，并且是有效调节结合转录物的子集（包括TDP-43 mRNA的自身调节）所需的。我们确定RBP缩合可以以结合区域特异性的方式发生，以选择性地调节转录组范围的RNA调控，这对重塑RNA网络的信号传导，疾病和进化具有影响。TDP-43突变体在多个尺度上以相似的程度影响缩合特性结合区缩合物在具有分散的富含UG基序的长RNA区域上形成RBPchimera-CLIP表明同聚体相互作用促进分子尺度缩合物缩合选择性地调节TDP-43的调节能力;例如，RNA结合蛋白的缩合倾向调节其与转录组中特定RNA区域的结合，并影响其RNA加工功能。这些“结合区缩合物”的形成，由分散在长RNA区域的特定基序类型促进，扩展了RNA结合可以选择性控制的方式，超出了典型的RNA结合结构域。
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. TDP-43 mutants affect condensation properties to a similar extent at multiple scales Binding-region condensates form on long RNA regions with dispersed UG-rich motifs RBPchimera-CLIP indicates homomeric interactions promote molecular-scale condensates Condensation selectively tunes the regulatory capacity of TDP-43; e.g., autoregulation The condensation propensity of an RNA-binding protein tunes its binding to specific RNA regions across the transcriptome and affects its RNA processing functions. Formation of these “binding-region condensates,” promoted by specific motif types that are dispersed across long RNA regions, expands the ways in which RNA binding can be selectively controlled beyond canonical RNA-binding domains.
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影响因子：
64.5
作者：
Attig J;Agostini F;Gooding C;Chakrabarti AM;Singh A;Haberman N;Zagalak JA;Emmett W;Smith CWJ;Luscombe NM;Ule J
通讯作者：
Ule J
DOI：
10.1042/bcj20160499
发表时间：
2017-04-07
期刊：
The Biochemical journal
影响因子：
--
作者：
Harrison AF;Shorter J
通讯作者：
Shorter J
影响因子：
4.8
作者：
Johnson, Brian S.;Snead, David;Gitler, Aaron D.
通讯作者：
Gitler, Aaron D.
影响因子：
16.6
作者：
Drobot B;Iglesias-Artola JM;Le Vay K;Mayr V;Kar M;Kreysing M;Mutschler H;Tang TD
通讯作者：
Tang TD
影响因子：
64.8
作者：
Jain A;Vale RD
通讯作者：
Vale RD