Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase

Free Radic Biol Med. 2018 Aug 20:124:214-220. doi: 10.1016/j.freeradbiomed.2018.06.008. Epub 2018 Jun 20.

Abstract

We report the crystal structures of the human (dihydro)lipoamide dehydrogenase (hLADH, hE3) and its disease-causing homodimer interface mutant D444V-hE3 at 2.27 and 1.84 Å resolution, respectively. The wild type structure is a unique uncomplexed, unliganded hE3 structure with the true canonical sequence. Based on the structural information a novel molecular pathomechanism is proposed for the impaired catalytic activity and enhanced capacity for reactive oxygen species generation of the pathogenic mutant. The mechanistic model involves a previously much ignored solvent accessible channel leading to the active site that might be perturbed also by other disease-causing homodimer interface substitutions of this enzyme.

Keywords: Alpha-ketoglutarate dehydrogenase complex; E3 deficiency; Lipoamide dehydrogenase; Oxidative stress; Pathogenic mutation; Protein structure; Pyruvate dehydrogenase complex; Reactive oxygen species; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Crystallography, X-Ray
  • Dihydrolipoamide Dehydrogenase / chemistry*
  • Dihydrolipoamide Dehydrogenase / genetics*
  • Humans
  • Models, Molecular
  • Mutant Proteins / chemistry*
  • Mutant Proteins / genetics*
  • Mutation*
  • Protein Conformation

Substances

  • Mutant Proteins
  • Dihydrolipoamide Dehydrogenase