Glutamic acid 242 is a valve in the proton pump of cytochrome c oxidase

doi:10.1073/pnas.0800770105

Glutamic acid 242 is a valve in the proton pump of cytochrome c oxidase

*Helsinki Bioenergetics Group, Structural Biology and Biophysics Program, Institute of Biotechnology, University of Helsinki, Viikinkaari 1, P.O. Box 65, 00014, Helsinki, Finland; and
^†Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520

Edited by Harry B. Gray, California Institute of Technology, Pasadena, CA, and approved February 26, 2008 (received for review January 25, 2008)

Abstract

Aerobic life is based on a molecular machinery that utilizes oxygen as a terminal electron sink. The membrane-bound cytochrome c oxidase (CcO) catalyzes the reduction of oxygen to water in mitochondria and many bacteria. The energy released in this reaction is conserved by pumping protons across the mitochondrial or bacterial membrane, creating an electrochemical proton gradient that drives production of ATP. A crucial question is how the protons pumped by CcO are prevented from flowing backwards during the process. Here, we show by molecular dynamics simulations that the conserved glutamic acid 242 near the active site of CcO undergoes a protonation state-dependent conformational change, which provides a valve in the pumping mechanism. The valve ensures that at any point in time, the proton pathway across the membrane is effectively discontinuous, thereby preventing thermodynamically favorable proton back-leakage while maintaining an overall high efficiency of proton translocation. Suppression of proton leakage is particularly important in mitochondria under physiological conditions, where production of ATP takes place in the presence of a high electrochemical proton gradient.

Footnotes

^‡To whom correspondence should be addressed. E-mail: marten.wikstrom{at}helsinki.fi
Author contributions: V.R.I.K., G.H., and M.W. designed research; V.R.I.K. performed research; V.R.I.K., M.I.V., G.H., and M.W. analyzed data; and V.R.I.K., G.H., and M.W. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
↵ § The numbering of amino acids is based on subunit I of CcO from bovine heart mitochondria.