ALS-causing D169G mutation disrupts the ATP-binding capacity of TDP-43 RRM1 domain

Biochem Biophys Res Commun. 2020 Apr 2;524(2):459-464. doi: 10.1016/j.bbrc.2020.01.122. Epub 2020 Jan 30.


TDP-43 inclusion is a pathological hallmark for ∼97% ALS and ∼45% FTD patients. So far, >50 ALS-causing mutations have been identified, most of which are hosted by the intrinsically-disordered prion-like domain. The D169G mutation is the only one within the well-folded RRM1 domain, which, however, induces no significant change of the crystal structure and even slightly enhances the thermodynamic stability. Therefore, the mechanism for D169G to enhance the cytotoxicity remains elusive. Here by NMR, we reveal for the first time: 1) D169G does trigger significant dynamic changes for a cluster of residues. 2) Very unexpectedly, D169G disrupts the ATP-binding capacity of RRM1 although the ATP-binding pocket is on the back side of the mutation site. Taken together with our previous results, the current study provides a potential mechanism to rationalize enhancement of the TDP-43 cytotoxicity by D169G and highlights again the key roles of ATP in neurodegenerative diseases and ageing.

Keywords: ALS; ATP; Adenosine triphosphate; Amyotrophic lateral sclerosis; D169G mutation; NMR spectroscopy; RNA-recognition motif; RRM; TAR-DNA binding protein-43; TDP-43.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Humans
  • Models, Molecular
  • Point Mutation*
  • Protein Binding
  • Protein Domains


  • DNA-Binding Proteins
  • TARDBP protein, human
  • Adenosine Triphosphate