TY  - JOUR
A1  - Galemou Yoga, Etienne
A1  - Parey, Kristian
A1  - Djurabekova, Amina
A1  - Haapanen, Outi
A1  - Siegmund, Karin
A1  - Zwicker, Klaus
A1  - Sharma, Vivek
A1  - Zickermann, Volker
A1  - Angerer, Heike
T1  - Essential role of accessory subunit LYRM6 in the mechanism of mitochondrial complex I
T2  - Nature Communications
N2  - 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 (β1-β2S2 loop), ND1 (TMH5-6ND1 loop) and ND3 (TMH1-2ND3 loop) were suggested to be critical for its proton pumping mechanism. Here, we show that stabilization of the TMH1-2ND3 loop by accessory subunit LYRM6 (NDUFA6) is pivotal for energy conversion by mitochondrial complex I. We determined the high-resolution structure of inactive mutant F89ALYRM6 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.
KW  - Bioenergetics
KW  - Computational biophysics
KW  - Cryoelectron microscopy
KW  - Energy metabolism
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/76127
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-761274
SN  - 2041-1723
N1  - Open Access funding enabled and organized by Projekt DEAL.
N1  - Data availability
The cryo-EM structures of complex I mutant F89ALYRM6 has been deposited in the PDB with PDB ID 6Y79 (Cryo-EM structure of a respiratory complex I F89A mutant) and the respective cryo-EM maps in the EMDB under accession numbers EMD-10711 (Cryo-EM structure of a respiratory complex I F89A mutant). All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Information. Additional data related to this paper may be requested from the authors. Source data are provided with this paper.
VL  - 11
IS  - art. 6008
SP  - 1
EP  - 8
PB  - Nature Publishing Group UK
CY  - [London]
ER  -