title: Gating of proton and water transfer in the respiratory enzyme cytochrome c oxidase.
abstract: The membrane-bound enzyme cytochrome c oxidase is responsible for cell respiration in aerobic organisms and conserves free energy from O2 reduction into an electrochemical proton gradient by coupling the redox reaction to proton-pumping across the membrane. O2 reduction produces water at the bimetallic heme a3/CuB active site next to a hydrophobic cavity deep within the membrane. Water molecules in this cavity have been suggested to play an important role in the proton-pumping mechanism. Here, we show by molecular dynamics simulations that the conserved arginine/heme a3 delta-propionate ion pair provides a gate, which exhibits reversible thermal opening that is governed by the redox state and the water molecules in the cavity. An important role of this gate in the proton-pumping mechanism is supported by site-directed mutagenesis experiments. Transport of the product water out of the enzyme must be rigidly controlled to prevent water-mediated proton leaks that could compromise the proton-pumping function. Exit of product water is observed through the same arginine/propionate gate, which provides an explanation for the observed extraordinary spatial specificity of water expulsion from the enzyme.
authors: Helsinki Bioenergetics Group, Institute of Biotechnology, Program for Structural Biology and Biophysics, University of Helsinki, PB 65 (Viikinkaari 1), 00014 Helsinki, Finland. marten.wikstrom@helsinki.fi
authors: Mårten
authors: M
authors: Wikström
authors: Camilla
authors: C
authors: Ribacka
authors: Mika
authors: M
authors: Molin
authors: Liisa
authors: L
authors: Laakkonen
authors: Michael
authors: M
authors: Verkhovsky
authors: Anne
authors: A
authors: Puustinen
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002417:Cattle; D003198:Computer Simulation; D003576:Electron Transport Complex IV / Q000737:chemistry* / Q000235:genetics; D006418:Heme / Q000031:analogs & derivatives / Q000378:metabolism; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D010231:Paracoccus denitrificans; D011422:Propionates / Q000378:metabolism; D017494:Proton Pumps / Q000502:physiology*; D014867:Water / Q000737:chemistry / Q000502:physiology*
chemical_list: D011422:Propionates; D017494:Proton Pumps; D014867:Water; C027728:heme a; D006418:Heme; D001120:Arginine; D003576:Electron Transport Complex IV