scholarly journals How cardiolipin modulates the dynamics of respiratory complex I

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1850 ◽  
Author(s):  
Alexander Jussupow ◽  
Andrea Di Luca ◽  
Ville R. I. Kaila
Keyword(s):  
Conformational Changes ◽  
Complex I ◽  
Specific Interaction ◽  
Proton Pumping ◽  
Respiratory Enzymes ◽  
Respiratory Complex ◽  
Respiratory Chains ◽  
Membrane Bound ◽  
Respiratory Complex I ◽  
Structure And Activity

Cardiolipin modulates the activity of membrane-bound respiratory enzymes that catalyze biological energy transduction. The respiratory complex I functions as the primary redox-driven proton pump in mitochondrial and bacterial respiratory chains, and its activity is strongly enhanced by cardiolipin. However, despite recent advances in the structural biology of complex I, cardiolipin-specific interaction mechanisms currently remain unknown. On the basis of millisecond molecular simulations, we suggest that cardiolipin binds to proton-pumping subunits of complex I and induces global conformational changes that modulate the accessibility of the quinone substrate to the enzyme. Our findings provide key information on the coupling between complex I dynamics and activity and suggest how biological membranes modulate the structure and activity of proteins.

Mammalian Respiratory Complex I Through the Lens of Cryo-EM

2019 ◽  
Vol 48 (1) ◽  
pp. 165-184 ◽  
Author(s):  
Ahmed-Noor A. Agip ◽  
James N. Blaza ◽  
Justin G. Fedor ◽  
Judy Hirst
Keyword(s):  
Complex I ◽  
Catalytic Mechanism ◽  
Structural Data ◽  
Proton Pumping ◽  
Nadh:Ubiquinone Oxidoreductase ◽  
Respiratory Complex ◽  
Data Collection Strategy ◽  
Structural Work ◽  
Membrane Bound ◽  
Respiratory Complex I

Single-particle electron cryomicroscopy (cryo-EM) has led to a revolution in structural work on mammalian respiratory complex I. Complex I (mitochondrial NADH:ubiquinone oxidoreductase), a membrane-bound redox-driven proton pump, is one of the largest and most complicated enzymes in the mammalian cell. Rapid progress, following the first 5-Å resolution data on bovine complex I in 2014, has led to a model for mouse complex I at 3.3-Å resolution that contains 96% of the 8,518 residues and to the identification of different particle classes, some of which are assigned to biochemically defined states. Factors that helped improve resolution, including improvements to biochemistry, cryo-EM grid preparation, data collection strategy, and image processing, are discussed. Together with recent structural data from an ancient relative, membrane-bound hydrogenase, cryo-EM on mammalian complex I has provided new insights into the proton-pumping machinery and a foundation for understanding the enzyme's catalytic mechanism.

scholarly journals Deactivation blocks proton pathways in the mitochondrial complex I

2021 ◽  
Vol 118 (29) ◽  
pp. e2019498118
Author(s):  
Michael Röpke ◽  
Daniel Riepl ◽  
Patricia Saura ◽  
Andrea Di Luca ◽  
Max E. Mühlbauer ◽  
...  
Keyword(s):  
Proton Transfer ◽  
Conformational Changes ◽  
Complex I ◽  
Large Scale ◽  
Proton Pumping ◽  
Cellular Respiration ◽  
Transmembrane Helices ◽  
Membrane Bound ◽  
Respiratory Complex I ◽  
Microscopy Data

Cellular respiration is powered by membrane-bound redox enzymes that convert chemical energy into an electrochemical proton gradient and drive the energy metabolism. By combining large-scale classical and quantum mechanical simulations with cryo-electron microscopy data, we resolve here molecular details of conformational changes linked to proton pumping in the mammalian complex I. Our data suggest that complex I deactivation blocks water-mediated proton transfer between a membrane-bound quinone site and proton-pumping modules, decoupling the energy-transduction machinery. We identify a putative gating region at the interface between membrane domain subunits ND1 and ND3/ND4L/ND6 that modulates the proton transfer by conformational changes in transmembrane helices and bulky residues. The region is perturbed by mutations linked to human mitochondrial disorders and is suggested to also undergo conformational changes during catalysis of simpler complex I variants that lack the “active”-to-“deactive” transition. Our findings suggest that conformational changes in transmembrane helices modulate the proton transfer dynamics by wetting/dewetting transitions and provide important functional insight into the mammalian respiratory complex I.

scholarly journals Functional Water Wires Catalyze Long-Range Proton Pumping in the Mammalian Respiratory Complex I

2020 ◽  
Vol 142 (52) ◽  
pp. 21758-21766
Author(s):  
Michael Röpke ◽  
Patricia Saura ◽  
Daniel Riepl ◽  
Maximilian C. Pöverlein ◽  
Ville R. I. Kaila
Keyword(s):  
Long Range ◽  
Complex I ◽  
Proton Pumping ◽  
Respiratory Complex ◽  
Respiratory Complex I

scholarly journals Redox-induced activation of the proton pump in the respiratory complex I

2015 ◽  
Vol 112 (37) ◽  
pp. 11571-11576 ◽  
Author(s):  
Vivek Sharma ◽  
Galina Belevich ◽  
Ana P. Gamiz-Hernandez ◽  
Tomasz Róg ◽  
Ilpo Vattulainen ◽  
...  
Keyword(s):  
Proton Pump ◽  
Conformational Changes ◽  
Complex I ◽  
Large Scale ◽  
Reductase Activity ◽  
Proton Pumping ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Respiratory Chains ◽  
Dynamics Simulations

Complex I functions as a redox-linked proton pump in the respiratory chains of mitochondria and bacteria, driven by the reduction of quinone (Q) by NADH. Remarkably, the distance between the Q reduction site and the most distant proton channels extends nearly 200 Å. To elucidate the molecular origin of this long-range coupling, we apply a combination of large-scale molecular simulations and a site-directed mutagenesis experiment of a key residue. In hybrid quantum mechanics/molecular mechanics simulations, we observe that reduction of Q is coupled to its local protonation by the His-38/Asp-139 ion pair and Tyr-87 of subunit Nqo4. Atomistic classical molecular dynamics simulations further suggest that formation of quinol (QH2) triggers rapid dissociation of the anionic Asp-139 toward the membrane domain that couples to conformational changes in a network of conserved charged residues. Site-directed mutagenesis data confirm the importance of Asp-139; upon mutation to asparagine the Q reductase activity is inhibited by 75%. The current results, together with earlier biochemical data, suggest that the proton pumping in complex I is activated by a unique combination of electrostatic and conformational transitions.

The coupling mechanism of mammalian respiratory complex I

Science ◽  
2020 ◽  
Vol 370 (6516) ◽  
pp. eabc4209 ◽  
Author(s):  
Domen Kampjut ◽  
Leonid A. Sazanov
Keyword(s):  
Conformational Changes ◽  
Complex I ◽  
Electrostatic Interactions ◽  
Proton Translocation ◽  
Proton Pumping ◽  
State Transitions ◽  
Coupling Mechanism ◽  
Cryo Electron Microscopy ◽  
Open Conformation ◽  
Respiratory Complex I

Mitochondrial complex I couples NADH:ubiquinone oxidoreduction to proton pumping by an unknown mechanism. Here, we present cryo–electron microscopy structures of ovine complex I in five different conditions, including turnover, at resolutions up to 2.3 to 2.5 angstroms. Resolved water molecules allowed us to experimentally define the proton translocation pathways. Quinone binds at three positions along the quinone cavity, as does the inhibitor rotenone that also binds within subunit ND4. Dramatic conformational changes around the quinone cavity couple the redox reaction to proton translocation during open-to-closed state transitions of the enzyme. In the induced deactive state, the open conformation is arrested by the ND6 subunit. We propose a detailed molecular coupling mechanism of complex I, which is an unexpected combination of conformational changes and electrostatic interactions.

scholarly journals Phylogeny and Evolutionary History of Respiratory Complex I Proteins in Melainabacteria

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 929
Author(s):  
Christen Grettenberger ◽  
Dawn Y. Sumner ◽  
Jonathan A. Eisen ◽  
Anne D. Jungblut ◽  
Tyler J. Mackey
Keyword(s):  
Complex I ◽  
Evolutionary History ◽  
Oxygenic Photosynthesis ◽  
Aerobic Respiration ◽  
Respiratory Complex ◽  
Earth’S Atmosphere ◽  
History Of ◽  
Respiratory Chains ◽  
Respiratory Complex I ◽  
Earth's Atmosphere

The evolution of oxygenic photosynthesis was one of the most transformative evolutionary events in Earth’s history, leading eventually to the oxygenation of Earth’s atmosphere and, consequently, the evolution of aerobic respiration. Previous work has shown that the terminal electron acceptors (complex IV) of aerobic respiration likely evolved after the evolution of oxygenic photosynthesis. However, complex I of the respiratory complex chain can be involved in anaerobic processes and, therefore, may have pre-dated the evolution of oxygenic photosynthesis. If so, aerobic respiration may have built upon respiratory chains that pre-date the rise of oxygen in Earth’s atmosphere. The Melainabacteria provide a unique opportunity to examine this hypothesis because they contain genes for aerobic respiration but likely diverged from the Cyanobacteria before the evolution of oxygenic photosynthesis. Here, we examine the phylogenies of translated complex I sequences from 44 recently published Melainabacteria metagenome assembled genomes and genomes from other Melainabacteria, Cyanobacteria, and other bacterial groups to examine the evolutionary history of complex I. We find that complex I appears to have been present in the common ancestor of Melainabacteria and Cyanobacteria, supporting the idea that aerobic respiration built upon respiratory chains that pre-date the evolution of oxygenic photosynthesis and the rise of oxygen.

scholarly journals Quinone binding in respiratory complex I: Going through the eye of a needle. The squeeze-in mechanism of passing the narrow entrance of the quinone site

2021 ◽  
Author(s):  
Nithin Dhananjayan ◽  
Panyue Wang ◽  
Igor Leontyev ◽  
Alexei A. Stuchebrukhov
Keyword(s):  
Conformational Changes ◽  
Complex I ◽  
Respiratory Complex ◽  
Quinone Binding ◽  
Bacterial Enzyme ◽  
Respiratory Complex I ◽  
Electron Reduction ◽  
Pass Through ◽  
Dynamics Simulations ◽  
Ubiquinone Binding

AbstractAt the joint between the membrane and hydrophilic arms of the enzyme, the structure of the respiratory complex I reveals a tunnel-like Q-chamber for ubiquinone binding and reduction. The narrow entrance of the quinone chamber located in ND1 subunit forms a bottleneck (eye of a needle) which in all resolved structures was shown to be too small for a bulky quinone to pass through, and it was suggested that a conformational change is required to open the channel. The closed bottleneck appears to be a well-established feature of all structures reported so-far, both for the so-called open and closed states of the enzyme, with no indication of a stable open state of the bottleneck. We propose a squeeze-in mechanism of the bottleneck passage, where dynamic thermal conformational fluctuations allow quinone to get in and out. Here, using molecular dynamics simulations of the bacterial enzyme, we have identified collective conformational changes that open the quinone chamber bottleneck. The model predicts a significant reduction—due to a need for a rare opening of the bottleneck—of the effective bi-molecular rate constant, in line with the available kinetic data. We discuss possible reasons for such a tight control of the quinone passage into the binding chamber and mechanistic consequences for the quinone two-electron reduction. Graphic abstract

scholarly journals S4.20 Substrate crosstalk involving conformational changes in E. coli respiratory complex I

2008 ◽  
Vol 1777 ◽  
pp. S37
Author(s):  
Katerina Dörner ◽  
Daniel Schneider ◽  
Stefan Stolpe ◽  
Bettina Böttcher ◽  
Petra Hellwig ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Complex I ◽  
E Coli ◽  
Respiratory Complex ◽  
Respiratory Complex I
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