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

Eszter Szabo, Reka Mizsei, Piotr Wilk, Zsofia Zambo, Beata Torocsik, Manfred S. Weiss, Vera Adam-Vizi, Attila Ambrus

Research output: Article

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)214-220
Number of pages7
JournalFree Radical Biology and Medicine
Volume124
DOIs
Publication statusPublished - aug. 20 2018

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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