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Structural insight into the type-II mitochondrial NADH dehydrogenases.

Authors :
Feng, Yue
Li, Wenfei
Li, Jian
Wang, Jiawei
Ge, Jingpeng
Xu, Duo
Liu, Yanjing
Wu, Kaiqi
Zeng, Qingyin
Wu, Jia-Wei
Tian, Changlin
Zhou, Bing
Yang, Maojun
Source :
Nature; 11/15/2012, Vol. 491 Issue 7424, p478-482, 5p, 3 Color Photographs
Publication Year :
2012

Abstract

The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex?I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD<superscript>+</superscript> homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex?I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex?I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ<subscript>I</subscript> and UQ<subscript>II</subscript>) in Ndi1. NADH and UQ<subscript>I</subscript> can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ<subscript>I</subscript> interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ<subscript>I</subscript> complex to UQ<subscript>II</subscript>. Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00280836
Volume :
491
Issue :
7424
Database :
Complementary Index
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
83403864
Full Text :
https://doi.org/10.1038/nature11541