期刊
NUCLEIC ACIDS RESEARCH
卷 37, 期 6, 页码 1799-1808出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkp013
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资金
- Academia Sinica and the National Science Council, Taiwan, ROC
- National Synchrotron Radiation Research Center [BL-13B1, BL-13C1]
- National Research Program for Genomic Medicine
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 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-43s TG/UG preference in nucleic acids binding. It also reveals that RRM2 domain has an atypical RRM-fold with an additional -strand involved in making proteinprotein interactions. This self association of RRM2 domains produced thermal-stable RRM2 assemblies with a melting point greater than 85C 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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