ALS-linked TDP-43 mutations interfere with the recruitment of RNA recognition motifs to G-quadruplex RNA.
ALS-linked TDP-43 mutations interfere with the recruitment of RNA recognition motifs to G-quadruplex RNA.
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DOI：
10.1038/s41598-023-33172-5
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发表时间：
2023-04-12
影响因子：
4.6
通讯作者：
Ishihama, Akira
中科院分区：
文献类型：
--
作者：
Ishiguro, Akira;Ishihama, Akira
TDP-43是散发性和家族性肌萎缩侧索硬化症（ALS）中的主要病理蛋白，并介导mRNA命运。TDP-43功能障碍导致运动神经元的进行性变性，其细节仍然难以捉摸。阐明RNA结合的分子机制可以增强我们对这种毁灭性疾病的理解。我们观察到TDP-43的富含甘氨酸（GR）的区域与其RNA识别基序（RRM）一起参与G-四链体（G4）-RNA的初始识别和结合。在这项研究中，我们对这些分子内RNA结合模块进行了分子解剖。我们证实GR区ALS连锁突变导致G4结构改变。相反，GR区的氨基酸取代改变了蛋白质结构，但并没有使与G4-RNA的相互作用无效。基于这些观察结果，我们得出结论，这些突变引起的G4结构畸变干扰RRM募集并导致TDP-43功能障碍。RRM和GR区域之间的这种分子内组织调节整体G4结合特性。
TDP-43 is a major pathological protein in sporadic and familial amyotrophic lateral sclerosis (ALS) and mediates mRNA fate. TDP-43 dysfunction leads to causes progressive degeneration of motor neurons, the details of which remain elusive. Elucidation of the molecular mechanisms of RNA binding could enhance our understanding of this devastating disease. We observed the involvement of the glycine-rich (GR) region of TDP-43 in the initial recognition and binding of G-quadruplex (G4)-RNA in conjunction with its RNA recognition motifs (RRM). We performed a molecular dissection of these intramolecular RNA-binding modules in this study. We confirmed that the ALS-linked mutations in the GR region lead to alteration in the G4 structure. In contrast, amino acid substitutions in the GR region alter the protein structure but do not void the interaction with G4-RNA. Based on these observations, we concluded that the structural distortion of G4 caused by these mutations interferes with RRM recruitment and leads to TDP-43 dysfunction. This intramolecular organization between RRM and GR regions modulates the overall G4-binding properties.
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影响因子：
5.3
作者：
Kapeli K;Martinez FJ;Yeo GW
通讯作者：
Yeo GW
影响因子：
14.9
作者：
Micsonai, Andras;Moussong, Eva;Wien, Frank;Boros, Eszter;Vadaszi, Henrietta;Murvai, Nikoletta;Lee, Young-Ho;Molnar, Tamas;Refregiers, Matthieu;Goto, Yuji;Tantos, Agnes;Kardos, Jozsef
通讯作者：
Kardos, Jozsef
影响因子：
2.1
作者：
Ishiguro, Akira;Kimura, Nobuyuki;Ishihama, Akira
通讯作者：
Ishihama, Akira
DOI：
10.1073/pnas.1008227107
发表时间：
2010-07-27
影响因子：
11.1
作者：
Ling, Shuo-Chien;Albuquerque, Claudio P.;Cleveland, Don W.
通讯作者：
Cleveland, Don W.
DOI：
10.1261/rna.056226.116
发表时间：
2016-12
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Jeng SC;Chan HH;Booy EP;McKenna SA;Unrau PJ
通讯作者：
Unrau PJ