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

Abstract

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 A 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 beta-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 degrees 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.

• Authors: Pan-Hsien Kuo, Lyudmila G Doudeva, Yi-Ting Wang, Che-Kun James Shen, Hanna S Yuan
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 37 Issue 6 Pg. 1799-808 (Apr 2009) ISSN: 1362-4962 [Electronic] England
• PMID: 19174564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Single-Stranded
• DNA-Binding Proteins
• RNA-Binding Proteins
• RNA
• DNA

Topics

• Amino Acid Sequence
• Binding Sites
• Crystallography, X-Ray
• DNA (chemistry, metabolism)
• DNA, Single-Stranded (chemistry, metabolism)
• DNA-Binding Proteins (chemistry, metabolism)
• Dimerization
• Models, Molecular
• Molecular Sequence Data
• Protein Binding
• Protein Interaction Domains and Motifs
• Protein Multimerization
• Protein Structure, Tertiary
• RNA (chemistry, metabolism)
• RNA-Binding Proteins (chemistry, metabolism)
• Temperature