Nucleic Acids Research Advance Access originally published online on January 27, 2009
Nucleic Acids Research 2009 37(6):1799-1808; doi:10.1093/nar/gkp013
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Nucleic Acids Research, 2009, Vol. 37, No. 6 1799-1808
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Structural insights into TDP-43 in nucleic-acid binding and domain interactions
1Institute of Bioinformatics and Structural Biology, National Tsing Hua University, 2Institute of Molecular Biology, 3Taiwan International Graduate Program, Chemical Biology and Molecular Biophysics, Academia Sinica and 4Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University, Taipei, Taiwan, ROC
*To whom correspondence should be addressed. Tel: +886 2 27884151; Fax: +886 2 27826085; Email: hanna{at}sinica.edu.tw
Received October 14, 2008. Revised November 27, 2008. Accepted January 7, 2009.
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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