Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells.
Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells.
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DOI：
10.1126/science.1254917
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发表时间：
2014-09-05
期刊：
影响因子：
--
通讯作者：
McKnight SL
中科院分区：
文献类型：
--
作者：
Kwon I;Xiang S;Kato M;Wu L;Theodoropoulos P;Wang T;Kim J;Yun J;Xie Y;McKnight SL
许多控制前体mRNA剪接的RNA调节蛋白含有丝氨酸：精氨酸（SR）重复序列。在这里，我们发现，这些SR域绑定水凝胶液滴组成的纤维聚合物的低复杂性结构域的异质性核糖核蛋白A2（hnRNPA 2）。水凝胶结合逆转后的SR结构域的磷酸化的CDC 2样激酶1和2（CLK 1/2）。将丝氨酸改变为甘氨酸的SR结构域的突变变体（SR-至-GR变体）也与hnRNPA 2水凝胶结合，但不受CLK 1/2的影响。当在哺乳动物细胞中表达时，这些变体结合核仁。与神经退行性疾病中改变的C9 ORF 72基因相关的扩展重复序列的正义和反义转录物的翻译产物编码GRN和PRN重复序列多肽。两种肽均与hnRNPA 2水凝胶结合，不依赖于CLK 1/2活性。当应用于培养细胞时，两种肽进入细胞，迁移到细胞核，结合核仁，并毒化RNA生物合成，导致细胞死亡。
Many RNA regulatory proteins controlling pre-mRNA splicing contain serine:arginine (SR) repeats. Here we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels, but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9ORF72 gene altered in neurodegenerative disease encode GRN and PRN repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death.
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影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
影响因子：
7.8
作者：
Bubulya, PA;Prasanth, KV;Spector, DL
通讯作者：
Spector, DL
影响因子：
3.7
作者：
Duncan, PI;Stojdl, DF;Bell, JC
通讯作者：
Bell, JC
DOI：
10.1083/jcb.107.3.841
发表时间：
1988-09
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dingwall C;Robbins J;Dilworth SM;Roberts B;Richardson WD
通讯作者：
Richardson WD
影响因子：
10.5
作者：
ZAHLER, AM;LANE, WS;ROTH, MB
通讯作者：
ROTH, MB