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

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Yksityiskohdat

AlkuperäiskieliEnglanti
Sivut11571-11576
Sivumäärä6
JulkaisuProceedings of the National Academy of Sciences of the United States of America
Vuosikerta112
Numero37
DOI - pysyväislinkit
TilaJulkaistu - 15 syyskuuta 2015
OKM-julkaisutyyppiA1 Alkuperäisartikkeli

Tiivistelmä

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.

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