Structural insights into TDP-43 in nucleic-acid binding and domain interactions.
Structural insights into TDP-43 in nucleic-acid binding and domain interactions.
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DOI：
10.1093/nar/gkp013
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发表时间：
2009-04
影响因子：
14.9
通讯作者：
Yuan HS
中科院分区：
文献类型：
--
作者：
Kuo PH;Doudeva LG;Wang YT;Shen CK;Yuan HS
TDP-43是一种致病蛋白：其与富含UG的RNA结合的正常功能与囊性纤维化有关，其C末端片段在脑细胞中的包含与额颞叶变性（FTLD）和肌萎缩侧索硬化症（ALS）直接相关。在这里，我们报告了TDP-43的C-末端RRM 2结构域与单链DNA复合的1.65 kDa晶体结构。我们发现，TDP-43是一个二聚体蛋白质与两个RRM结构域，都参与DNA和RNA结合。晶体结构揭示了TDP-43在核酸结合中的TG/UG偏好的基础。它还揭示了RRM 2结构域具有非典型的RRM-fold，其具有参与蛋白质-蛋白质相互作用的额外β链。RRM 2结构域的这种自缔合产生了热稳定的RRM 2组装体，其熔点大于85°C，如在生理条件下通过圆二色性监测的。因此，这些研究表征了TDP-43与核酸之间的识别以及RRM 2自缔合的模式，并为理解TDP-43在囊性纤维化和与TDP-43蛋白质病相关的神经退行性疾病中的作用提供了分子模型。
TDP-43 is a pathogenic protein: its normal function in binding to UG-rich RNA is related to cystic fibrosis, and inclusion of its C-terminal fragments in brain cells is directly linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Here we report the 1.65 Å crystal structure of the C-terminal RRM2 domain of TDP-43 in complex with a single-stranded DNA. We show that TDP-43 is a dimeric protein with two RRM domains, both involved in DNA and RNA binding. The crystal structure reveals the basis of TDP-43's TG/UG preference in nucleic acids binding. It also reveals that RRM2 domain has an atypical RRM-fold with an additional β-strand involved in making protein–protein interactions. This self association of RRM2 domains produced thermal-stable RRM2 assemblies with a melting point greater than 85°C as monitored by circular dichroism at physiological conditions. These studies thus characterize the recognition between TDP-43 and nucleic acids and the mode of RRM2 self association, and provide molecular models for understanding the role of TDP-43 in cystic fibrosis and the neurodegenerative diseases related to TDP-43 proteinopathy.
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影响因子：
11.4
作者：
Crichlow, Gregg V.;Zhou, Hongwen;Hsiao, Hsin-hao;Frederick, Kendra B.;Debrosse, Maxime;Yang, Yuande;Folta-Stogniew, Ewa J.;Chung, Hye-Jung;Fan, Chengpeng;De La Cruz, Enrique M.;Levens, David;Lolis, Elias;Braddock, Demetrios
通讯作者：
Braddock, Demetrios
影响因子：
64.8
作者：
OUBRIDGE, C;ITO, N;NAGAI, K
通讯作者：
NAGAI, K
TDP43 是一种人类低分子量神经丝蛋白（hNFL）mRNA 结合蛋白
影响因子：
3.5
作者：
Strong, Michael J.;Volkening, Kathryn;Shoesmith, Christen
通讯作者：
Shoesmith, Christen
影响因子：
6
作者：
Cairns, Nigel J.;Neumann, Manuela;Mackenzie, Ian R. A.
通讯作者：
Mackenzie, Ian R. A.
影响因子：
4.8
作者：
Buratti, E;Brindisi, A;Baralle, FE
通讯作者：
Baralle, FE