6i4p
Crystal structure of the disease-causing G194C mutant of the human dihydrolipoamide dehydrogenase
Structural highlights
DiseaseDLDH_HUMAN Note=Defects in DLD are involved in the development of congenital infantile lactic acidosis. Defects in DLD are a cause of maple syrup urine disease (MSUD) [MIM:248600. MSUD is characterized by mental and physical retardation, feeding problems and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. FunctionDLDH_HUMAN Lipoamide dehydrogenase is a component of the glycine cleavage system as well as of the alpha-ketoacid dehydrogenase complexes. Involved in the hyperactivation of spermatazoa during capacitation and in the spermatazoal acrosome reaction. Publication Abstract from PubMedHuman dihydrolipoamide dehydrogenase (hLADH, hE3) deficiency (OMIM# 246900) is an often prematurely lethal genetic disease usually caused by inactive or partially inactive hE3 variants. Here we report the crystal structure of wild-type hE3 at an unprecedented high resolution of 1.75 A and the structures of six disease-causing hE3 variants at resolutions ranging from 1.44 to 2.34 A. P453L proved to be the most deleterious substitution in structure as aberrations extensively compromised the active site. The most prevalent G194C-hE3 variant primarily exhibited structural alterations close to the substitution site, whereas the nearby cofactor-binding residues were left unperturbed. The G426E substitution mainly interfered with the local charge distribution introducing dynamics to the substitution site in the dimer interface; G194C and G426E both led to minor structural changes. The R460G, R447G, and I445M substitutions all perturbed a solvent accessible channel, the so-called H+/H2O channel, leading to the active site. Molecular pathomechanisms of enhanced reactive oxygen species (ROS) generation and impaired binding to multienzyme complexes were also addressed according to the structural data for the relevant mutations. In summary, we present here for the first time a comprehensive study that links three-dimensional structures of disease-causing hE3 variants to residual hLADH activities, altered capacities for ROS generation, compromised affinities for multienzyme complexes, and eventually clinical symptoms. Our results may serve as useful starting points for future therapeutic intervention approaches. Underlying molecular alterations in human dihydrolipoamide dehydrogenase deficiency revealed by structural analyses of disease-causing enzyme variants.,Szabo E, Wilk P, Nagy B, Zambo Z, Bui D, Weichsel A, Arjunan P, Torocsik B, Hubert A, Furey W, Montfort WR, Jordan F, Weiss MS, Adam-Vizi V, Ambrus A Hum Mol Genet. 2019 Jul 23. pii: 5537123. doi: 10.1093/hmg/ddz177. PMID:31334547[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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