کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1904451 1534628 2016 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structural alterations induced by ten disease-causing mutations of human dihydrolipoamide dehydrogenase analyzed by hydrogen/deuterium-exchange mass spectrometry: Implications for the structural basis of E3 deficiency
ترجمه فارسی عنوان
تغییرات ساختاری ناشی از ده جهش های بیماری زا از دهیدروژناز dihydrolipoamide انسانی آنالیز شده توسط طیف سنجی جرمی تبادل هیدروژن/دوتریوم : پیامدها برای اساس ساختاری کمبود E3
کلمات کلیدی
دهیدروژناز پیچیده ؛ دهیدروژناز پیرووات پیچیده ؛ زنجیره شاخه α-کتو پیچیده اسید دهیدروژناز؛ ، هیدروژناز،
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی سالمندی
چکیده انگلیسی


• Study of common E3 of human α-ketoglutarate and pyruvate dehydrogenase complexes.
• Effects of ten pathogenic mutations on human E3 structure examined by HDX-MS.
• Structural changes identified account for loss in cofactor binding and activity.
• Mutations lead to dysfunctional complexes and alter interactions in variants.
• HDX-MS results suggest structural sources of elevated ROS-generating capacities.

Pathogenic amino acid substitutions of the common E3 component (hE3) of the human alpha-ketoglutarate dehydrogenase and the pyruvate dehydrogenase complexes lead to severe metabolic diseases (E3 deficiency), which usually manifest themselves in cardiological and/or neurological symptoms and often cause premature death. To date, 14 disease-causing amino acid substitutions of the hE3 component have been reported in the clinical literature. None of the pathogenic protein variants has lent itself to high-resolution structure elucidation by X-ray or NMR. Hence, the structural alterations of the hE3 protein caused by the disease-causing mutations and leading to dysfunction, including the enhanced generation of reactive oxygen species by selected disease-causing variants, could only be speculated. Here we report results of an examination of the effects on the protein structure of ten pathogenic mutations of hE3 using hydrogen/deuterium-exchange mass spectrometry (HDX-MS), a new and state-of-the-art approach of solution structure elucidation. On the basis of the results, putative structural and mechanistic conclusions were drawn regarding the molecular pathogenesis of each disease-causing hE3 mutation addressed in this study.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1862, Issue 11, November 2016, Pages 2098–2109
نویسندگان
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