The RRM domain of human fused in sarcoma protein reveals a non-canonical nucleic acid binding site

Xuehui Liu, Chunyan Niu, Jintao Ren, Jiayu Zhang, Xiaodong Xie, Haining Zhu, Wei Feng, Weimin Gong

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Fused in sarcoma (FUS) is involved in many processes of RNA metabolism. FUS and another RNA binding protein, TDP-43, are implicated in amyotrophic lateral sclerosis (ALS). It is significant to characterize the RNA recognition motif (RRM) of FUS as its nucleic acid binding properties are unclear. More importantly, abolishing the RNA binding ability of the RRM domain of TDP43 was reported to suppress the neurotoxicity of TDP-43 in Drosophila. The sequence of FUS-RRM varies significantly from canonical RRMs, but the solution structure of FUS-RRM determined by NMR showed a similar overall folding as other RRMs. We found that FUS-RRM directly bound to RNA and DNA and the binding affinity was in the micromolar range as measured by surface plasmon resonance and NMR titration. The nucleic acid binding pocket in FUS-RRM is significantly distorted since several critical aromatic residues are missing. An exceptionally positively charged loop in FUS-RRM, which is not found in other RRMs, is directly involved in the RNA/DNA binding. Substituting the lysine residues in the unique KK loop impaired the nucleic acid binding and altered FUS subcellular localization. The results provide insights into the nucleic acid binding properties of FUS-RRM and its potential relevance to ALS.

Original languageEnglish (US)
Pages (from-to)375-385
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number2
DOIs
StatePublished - Feb 2013
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis
  • Fused in sarcoma
  • NMR
  • Nucleic acid binding
  • RNA recognition motif
  • Surface plasmon resonance

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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