Structural insights into TDP-43 in nucleic-acid binding and domain interactions

Pan Hsien Kuo, Lyudmila G. Doudeva, Yi Ting Wang, Che Kun James Shen, Hanna S. Yuan

研究成果: 雜誌貢獻文章同行評審

189 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)1799-1808
頁數10
期刊Nucleic Acids Research
37
發行號6
DOIs
出版狀態已發佈 - 2009
對外發佈

ASJC Scopus subject areas

  • 遺傳學

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