Possible roles of two quinone molecules in direct and indirect proton pumps of bovine heart NADH-quinone oxidoreductase (complex I)

Ohnishi, S. Tsuyoshi; Salerno, John C.; Ohnishi, Tomo̧ko

doi:10.1016/j.bbabio.2010.06.010

Cited by 38 publications

(27 citation statements)

References 37 publications

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“…In contrast, in complex I the electron and proton transfers are separated both kinetically and spatially. To explain this long-range coupling, both "direct" (redox-driven) and "indirect" (conformational-driven) mechanisms have been suggested, but the molecular principles of these mechanisms remain elusive (1,2,4,(17)(18)(19)(20)(21)(22).…”

Section: Significancementioning

confidence: 99%

Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I

Kaila

Wikström

Hummer

2014

Proc. Natl. Acad. Sci. U.S.A.

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Complex I serves as the primary electron entry point into the mitochondrial and bacterial respiratory chains. It catalyzes the reduction of quinones by electron transfer from NADH, and couples this exergonic reaction to the translocation of protons against an electrochemical proton gradient. The membrane domain of the enzyme extends ∼180 Å from the site of quinone reduction to the most distant proton pathway. To elucidate possible mechanisms of the long-range proton-coupled electron transfer process, we perform large-scale atomistic molecular dynamics simulations of the membrane domain of complex I from Escherichia coli. We observe spontaneous hydration of a putative proton entry channel at the NuoN/K interface, which is sensitive to the protonation state of buried glutamic acid residues. In hybrid quantum mechanics/classical mechanics simulations, we find that the observed water wires support rapid proton transfer from the protein surface to the center of the membrane domain. To explore the functional relevance of the pseudosymmetric inverted-repeat structures of the antiporter-like subunits NuoL/M/N, we constructed a symmetry-related structure of a possible alternateaccess state. In molecular dynamics simulations, we find the resulting structural changes to be metastable and reversible at the protein backbone level. However, the increased hydration induced by the conformational change persists, with water molecules establishing enhanced lateral connectivity and pathways for proton transfer between conserved ionizable residues along the center of the membrane domain. Overall, the observed watergated transitions establish conduits for the unidirectional proton translocation processes, and provide a possible coupling mechanism for the energy transduction in complex I.biological energy conversion | proton pumping | Grotthuss mechanism |

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Section: Significancementioning

confidence: 99%

Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I

Kaila

Wikström

Hummer

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The majority of stoichiometry measurements have been carried out on the mammalian enzyme (see, for example [1][2][3]) for which the four-protonsper-NADH stoichiometry is relatively well established: it is possible that mammalian complexes I pump two protons per catalytic half cycle (one through subunit ND4 and one through ND5), whereas fungal and bacterial complexes I may pump three (through subunits ND4, ND5 and ND2). Whether ND2 is directly active in proton translocation is thus a key fact in distinguishing extant mechanistic models for proton translocation by complex I (for example, [10,34]). Interestingly, it has been found recently that the c-ring of ATP synthase contains only eight subunits in vertebrates, and probably in many invertebrates, but between 10 and 15 subunits in fungi and eubacteria [37].…”

Section: Possible Implications For the Mechanism Of Complex Imentioning

confidence: 99%

“…Possible supporting roles include anchoring the lateral helix and promoting the coupling of proton and electron translocation, and ND2 has been suggested to bind ubiquinone also [23,34]. It is interesting to note that both the operation of the 'active-deactive transition' in complex I from higher metazoans, and the high affinity of these enzymes for rotenone [35,36], may be related to the truncation of ND2, although there is insufficient extant data for a definitive correlation to be drawn at present.…”

Section: Possible Implications For the Mechanism Of Complex Imentioning

confidence: 99%

Truncation of subunit ND2 disrupts the threefold symmetry of the antiporter‐like subunits in complex I from higher metazoans

Birrell

Hirst

2010

FEBS Letters

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a b s t r a c tThree of the conserved, membrane-bound subunits in NADH:ubiquinone oxidoreductase (complex I) are related to one another, and to Mrp sodium-proton antiporters. Recent structural analysis of two prokaryotic complexes I revealed that the three subunits each contain fourteen transmembrane helices that overlay in structural alignments: the translocation of three protons may be coordinated by a lateral helix connecting them together (Efremov, R.G., Baradaran, R. and Sazanov, L.A. (2010). The architecture of respiratory complex I. Nature 465, 441-447). Here, we show that in higher metazoans the threefold symmetry is broken by the loss of three helices from subunit ND2; possible implications for the mechanism of proton translocation are discussed.

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“…1) (8,11). Biochemical and structural studies suggest that the reduction of Q activates the proton pump via a conformationaldriven coupling mechanism, accompanied by electrostatic gating (2, 6-8, [12][13][14]. A recent study suggested that water-gated transitions and cooperative electrostatic couplings are also of importance in establishing a functional pump (15).…”

mentioning

confidence: 99%

“…chain, thus allowing for efficient eT (13,18 and references therein). This finding is consistent with earlier biochemical data, suggesting that the Q headgroup is in hydrogen-bonding contact with Tyr-87 of subunit Nqo4 (19).…”

mentioning

confidence: 99%

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

Sharma

Belevich

Gámiz‐Hernández

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

170

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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 (QH 2 ) 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.NADH-quinone oxidoreductase | electron transfer | molecular dynamics simulations | QM/MM simulations | cell respiration C omplex I (NADH-quinone oxidoreductase) is the largest (550-980 kDa) and one of the most enigmatic enzymes of the electron transport chains of mitochondria and bacteria. It catalyzes electron transfer (eT) from reduced nicotinamide adenine dinucleotide (NADH) to quinone (Q) and couples the reaction to translocation of three to four protons across the membrane (1, 2). The established electrochemical proton gradient is further used to synthesize adenosine triphosphate (ATP) for active transport (3). Due to its central role in cellular respiration, elucidating the catalytic mechanism of complex I is crucial for understanding the molecular principles of biological energy transduction and for unveiling the origins of many mitochondrial disorders (4).The electrons donated by NADH to complex I are transferred via flavin mononucleotide (FMN) to Q, bound at the lower edge of the hydrophilic domain at a distance of ∼80 Å from the FMN (Fig. 1). The eT process is mediated by seven to eight iron-sulfur (FeS) clusters, depending on the organism, and takes place in ∼100 μs (5). It is believed that the eT process does not couple to proton translocation, which is likely to occur on millisecond timescales (5, 6), but it is rather the oxidoreduction chemistry of the bound Q molecule that drives the proton pump (2, 5-9; cf. ref. 10).The proton-pumping machinery of complex I is located in the membrane domain of the enzyme (9) and is responsible for pumping three to four protons across the membrane (Fig. 1) (8, 11). Biochemical and structural studies suggest that the reduction of Q activates the proton pump via a conformationaldriven coupling mechanism, accompanied by electrostatic gating (2, 6-8, 12-14). A ...

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Possible roles of two quinone molecules in direct and indirect proton pumps of bovine heart NADH-quinone oxidoreductase (complex I)

Cited by 38 publications

References 37 publications

Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I

Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I

Truncation of subunit ND2 disrupts the threefold symmetry of the antiporter‐like subunits in complex I from higher metazoans

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

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