Structural Insights into TDP-43 in Nucleic Acid Binding and
Pathogenic Domain Aggregation
Pan-Hsien Kuo (郭邦賢)1,2, Lyudmila G. Doudeva2, Yi-Ting Wang (王宜婷)1,2,3,
Che-Kun James Shen (沈哲鯤)2, and Hanna S. Yuan (袁小琀)2,3,4
1
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu,
Taiwan
2
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
3
Taiwan International Graduate Program, Chemical Biology and Molecular Biophysics,
Academia Sinica, Taipei, Taiwan
4
Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University,
Taipei, Taiwan
TDP-43 is a pathogenic protein; its normal function in binding to UG-rich RNA is related to
cystic fibrosis, and its pathogenic inclusions in brain cells are directly linked to frontotemporal
lobar degeneration and amyotrophic lateral sclerosis. We show here that TDP-43 is a dimeric
protein with two RRM domains involved in DNA and RNA binding. The crystal structure of
TDP-43 RRM2 domain in complex with DNA reveals the basis of its preference for TG/UG-rich
sequences, and also shows that RRM2 domain has an additional unique β-strand capable of
atypical domain-domain interactions. When the RRM1 domain is cleaved, this unique β-strand
can be exposed, allowing aggregation via the RRM2 domain to form a “super β-helix” fibril
structure. Thermal melting studies monitored by circular dichroism further show that the pathogenic
RRM2 domain is highly stable with a melting point greater than 85 oC at physiological conditions.
All these results suggest that the mode of TDP-43 RRM2 self-association has broad implications for
understanding the non-amyloid aggregates in the neurodegenerative diseases related to TDP-43
proteinopathy.