Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I

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Galemou Yoga , E , Parey , K , Djurabekova , A , Haapanen , O , Siegmund , K , Zwicker , K , Sharma , V , Zickermann , V & Angerer , H 2020 , ' Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I ' , Nature Communications , vol. 11 , no. 1 , 6008 . https://doi.org/10.1038/s41467-020-19778-7

Title: Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I
Author: Galemou Yoga, Etienne; Parey, Kristian; Djurabekova, Amina; Haapanen, Outi; Siegmund, Karin; Zwicker, Klaus; Sharma, Vivek; Zickermann, Volker; Angerer, Heike
Other contributor: University of Helsinki, Materials Physics
University of Helsinki, Materials Physics
University of Helsinki, Department of Physics



Date: 2020-12-26
Language: eng
Number of pages: 8
Belongs to series: Nature Communications
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-020-19778-7
URI: http://hdl.handle.net/10138/324006
Abstract: Respiratory complex I catalyzes electron transfer from NADH to ubiquinone (Q) coupled to vectorial proton translocation across the inner mitochondrial membrane. Despite recent progress in structure determination of this very large membrane protein complex, the coupling mechanism is a matter of ongoing debate and the function of accessory subunits surrounding the canonical core subunits is essentially unknown. Concerted rearrangements within a cluster of conserved loops of central subunits NDUFS2 (beta 1-beta 2(S2) loop), ND1 (TMH5-6(ND1) loop) and ND3 (TMH1-2(ND3) loop) were suggested to be critical for its proton pumping mechanism. Here, we show that stabilization of the TMH1-2(ND3) loop by accessory subunit LYRM6 (NDUFA6) is pivotal for energy conversion by mitochondrial complex I. We determined the high-resolution structure of inactive mutant F89A(LYRM6) of eukaryotic complex I from the yeast Yarrowia lipolytica and found long-range structural changes affecting the entire loop cluster. In atomistic molecular dynamics simulations of the mutant, we observed conformational transitions in the loop cluster that disrupted a putative pathway for delivery of substrate protons required in Q redox chemistry. Our results elucidate in detail the essential role of accessory subunit LYRM6 for the function of eukaryotic complex I and offer clues on its redox-linked proton pumping mechanism. Respiratory complex I plays a key role in energy metabolism. Cryo-EM structure of a mutant accessory subunit LYRM6 from the yeast Yarrowia lipolytica and molecular dynamics simulations reveal conformational changes at the interface between LYRM6 and subunit ND3, propagated further into the complex. These findings offer insight into the mechanism of proton pumping by respiratory complex I.
Subject: GUI MEMBRANE-BUILDER
MOLECULAR-DYNAMICS
CRYSTAL-STRUCTURE
UBIQUINONE BINDING
49-KDA SUBUNIT
CRYO-EM
CHARMM
PROTEIN
OXIDOREDUCTASE
ORIENTATION
1182 Biochemistry, cell and molecular biology
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