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Structure of mycobacterial respiratory complex I

Oxidative phosphorylation, the combined activity of the electron transport chain (ETC) and adenosine triphosphate synthase, has emerged as a valuable target for the treatment of infection by Mycobacterium tuberculosis and other mycobacteria. The mycobacterial ETC is highly branched with multiple deh...

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Autores principales: Liang, Yingke, Plourde, Alicia, Bueler, Stephanie A., Liu, Jun, Brzezinski, Peter, Vahidi, Siavash, Rubinstein, John L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068793/
https://www.ncbi.nlm.nih.gov/pubmed/36952383
http://dx.doi.org/10.1073/pnas.2214949120
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author Liang, Yingke
Plourde, Alicia
Bueler, Stephanie A.
Liu, Jun
Brzezinski, Peter
Vahidi, Siavash
Rubinstein, John L.
author_facet Liang, Yingke
Plourde, Alicia
Bueler, Stephanie A.
Liu, Jun
Brzezinski, Peter
Vahidi, Siavash
Rubinstein, John L.
author_sort Liang, Yingke
collection PubMed
description Oxidative phosphorylation, the combined activity of the electron transport chain (ETC) and adenosine triphosphate synthase, has emerged as a valuable target for the treatment of infection by Mycobacterium tuberculosis and other mycobacteria. The mycobacterial ETC is highly branched with multiple dehydrogenases transferring electrons to a membrane-bound pool of menaquinone and multiple oxidases transferring electrons from the pool. The proton-pumping type I nicotinamide adenine dinucleotide (NADH) dehydrogenase (Complex I) is found in low abundance in the plasma membranes of mycobacteria in typical in vitro culture conditions and is often considered dispensable. We found that growth of Mycobacterium smegmatis in carbon-limited conditions greatly increased the abundance of Complex I and allowed isolation of a rotenone-sensitive preparation of the enzyme. Determination of the structure of the complex by cryoEM revealed the “orphan” two-component response regulator protein MSMEG_2064 as a subunit of the assembly. MSMEG_2064 in the complex occupies a site similar to the proposed redox-sensing subunit NDUFA9 in eukaryotic Complex I. An apparent purine nucleoside triphosphate within the NuoG subunit resembles the GTP-derived molybdenum cofactor in homologous formate dehydrogenase enzymes. The membrane region of the complex binds acyl phosphatidylinositol dimannoside, a characteristic three-tailed lipid from the mycobacterial membrane. The structure also shows menaquinone, which is preferentially used over ubiquinone by gram-positive bacteria, in two different positions along the quinone channel, comparable to ubiquinone in other structures and suggesting a conserved quinone binding mechanism.
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spelling pubmed-100687932023-09-23 Structure of mycobacterial respiratory complex I Liang, Yingke Plourde, Alicia Bueler, Stephanie A. Liu, Jun Brzezinski, Peter Vahidi, Siavash Rubinstein, John L. Proc Natl Acad Sci U S A Biological Sciences Oxidative phosphorylation, the combined activity of the electron transport chain (ETC) and adenosine triphosphate synthase, has emerged as a valuable target for the treatment of infection by Mycobacterium tuberculosis and other mycobacteria. The mycobacterial ETC is highly branched with multiple dehydrogenases transferring electrons to a membrane-bound pool of menaquinone and multiple oxidases transferring electrons from the pool. The proton-pumping type I nicotinamide adenine dinucleotide (NADH) dehydrogenase (Complex I) is found in low abundance in the plasma membranes of mycobacteria in typical in vitro culture conditions and is often considered dispensable. We found that growth of Mycobacterium smegmatis in carbon-limited conditions greatly increased the abundance of Complex I and allowed isolation of a rotenone-sensitive preparation of the enzyme. Determination of the structure of the complex by cryoEM revealed the “orphan” two-component response regulator protein MSMEG_2064 as a subunit of the assembly. MSMEG_2064 in the complex occupies a site similar to the proposed redox-sensing subunit NDUFA9 in eukaryotic Complex I. An apparent purine nucleoside triphosphate within the NuoG subunit resembles the GTP-derived molybdenum cofactor in homologous formate dehydrogenase enzymes. The membrane region of the complex binds acyl phosphatidylinositol dimannoside, a characteristic three-tailed lipid from the mycobacterial membrane. The structure also shows menaquinone, which is preferentially used over ubiquinone by gram-positive bacteria, in two different positions along the quinone channel, comparable to ubiquinone in other structures and suggesting a conserved quinone binding mechanism. National Academy of Sciences 2023-03-23 2023-03-28 /pmc/articles/PMC10068793/ /pubmed/36952383 http://dx.doi.org/10.1073/pnas.2214949120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Liang, Yingke
Plourde, Alicia
Bueler, Stephanie A.
Liu, Jun
Brzezinski, Peter
Vahidi, Siavash
Rubinstein, John L.
Structure of mycobacterial respiratory complex I
title Structure of mycobacterial respiratory complex I
title_full Structure of mycobacterial respiratory complex I
title_fullStr Structure of mycobacterial respiratory complex I
title_full_unstemmed Structure of mycobacterial respiratory complex I
title_short Structure of mycobacterial respiratory complex I
title_sort structure of mycobacterial respiratory complex i
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068793/
https://www.ncbi.nlm.nih.gov/pubmed/36952383
http://dx.doi.org/10.1073/pnas.2214949120
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