REAL

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

Szabó, Eszter and Mizsei, Réka and Wilk, P. and Zámbó, Zsófia and Törőcsik, Beáta and Ádám, Veronika and Ambrus, Attila (2018) Crystal structures of the disease-causing D444V mutant and the relevant wild type human dihydrolipoamide dehydrogenase. FREE RADICAL BIOLOGY AND MEDICINE, 124. pp. 214-220. ISSN 0891-5849

[img] Text
3407990_2018_Chrystal_structures_of_disease-causing_D444V.pdf
Restricted to Registered users only

Download (272kB) | Request a copy

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. © 2018 Elsevier Inc.

Item Type: Article
Uncontrolled Keywords: OXIDATIVE STRESS; Reactive oxygen species; X-RAY CRYSTALLOGRAPHY; protein structure; Lipoamide Dehydrogenase; Pyruvate Dehydrogenase Complex; Pathogenic mutation; E3 deficiency; Alpha-ketoglutarate dehydrogenase complex;
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában > R850-854 Experimental medicine / kisérleti orvostudomány
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 29 Jan 2019 11:00
Last Modified: 29 Jan 2019 11:00
URI: http://real.mtak.hu/id/eprint/90601

Actions (login required)

Edit Item Edit Item