A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43

Yoshiaki Furukawa, Yoh Suzuki, Mami Fukuoka, Kenichi Nagasawa, Kenta Nakagome, Hideaki Shimizu, Atsushi Mukaiyama, Shuji Akiyama

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein containing two consecutive RNA recognition motifs (RRM1 and RRM2) in tandem. Functional abnormality of TDP-43 has been proposed to cause neurodegeneration, but it remains obscure how the physiological functions of this protein are regulated. Here, we show distinct roles of RRM1 and RRM2 in the sequence-specific substrate recognition of TDP-43. RRM1 was found to bind a wide spectrum of ssDNA sequences, while no binding was observed between RRM2 and ssDNA. When two RRMs are fused in tandem as in native TDP-43, the fused construct almost exclusively binds ssDNA with a TG-repeat sequence. In contrast, such sequence-specificity was not observed in a simple mixture of RRM1 and RRM2. We thus propose that the spatial arrangement of multiple RRMs in DNA/RNA binding proteins provides steric effects on the substrate-binding site and thereby controls the specificity of its substrate nucleotide sequences.

Original languageEnglish
Article number20576
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Feb 3

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DNA-Binding Proteins
Nucleic Acids
RNA-Binding Proteins
Substrate Specificity
Binding Sites
Proteins

ASJC Scopus subject areas

  • General

Cite this

Furukawa, Y., Suzuki, Y., Fukuoka, M., Nagasawa, K., Nakagome, K., Shimizu, H., ... Akiyama, S. (2016). A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43. Scientific Reports, 6, [20576]. https://doi.org/10.1038/srep20576

A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43. / Furukawa, Yoshiaki; Suzuki, Yoh; Fukuoka, Mami; Nagasawa, Kenichi; Nakagome, Kenta; Shimizu, Hideaki; Mukaiyama, Atsushi; Akiyama, Shuji.

In: Scientific Reports, Vol. 6, 20576, 03.02.2016.

Research output: Contribution to journalArticle

Furukawa, Y, Suzuki, Y, Fukuoka, M, Nagasawa, K, Nakagome, K, Shimizu, H, Mukaiyama, A & Akiyama, S 2016, 'A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43', Scientific Reports, vol. 6, 20576. https://doi.org/10.1038/srep20576
Furukawa, Yoshiaki ; Suzuki, Yoh ; Fukuoka, Mami ; Nagasawa, Kenichi ; Nakagome, Kenta ; Shimizu, Hideaki ; Mukaiyama, Atsushi ; Akiyama, Shuji. / A molecular mechanism realizing sequence-specific recognition of nucleic acids by TDP-43. In: Scientific Reports. 2016 ; Vol. 6.
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