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Investigator

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Volker Zickermann
PD Dr.

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Structural Bioenergetics Group
Institute of Biochemistry II
Goethe University Medical School
Max-von-Laue-Str. 9
60438 Frankfurt am Main, Germany

Phone +49 (0)69 798-29575

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Redox-linked proton translocation by respiratory complex I


PD Dr. Volker Zickermann
, Structural Bioenergetics Group, Institute of Biochemistry II,
Goethe University Medical School


Mitochondrial complex I is the largest and most complex enzyme of the respiratory chain and plays a key role in aerobic energy metabolism. In addition to fourteen central subunits that execute redox-linked proton translocation, complex I comprises some 30 accessory subunits of largely unknown function. Complex I dysfunction has been linked with hereditary and degenerative disorders and generation of reactive oxygen species by complex I contributes to tissue damage in myocardial infarction. We have crystallized complex I from the aerobic yeast Yarrowia lipolytica and solved the structure at a resolution of 3.6 to 3.9 Å. The central subunits can be assigned to three functional modules, the N module for NADH oxidation, the Q module for ubiquinone reduction, and the P module for proton pumping. The major part of the P module shows an intriguing homology to Mrp type cation proton antiporters. A connection between the ubiquinone reduction site and four putative proton pump elements is formed by a central axis of basic and acidic residues. The X-ray structure suggests that the redox chemistry of ubiquinone is linked with conformational changes of the ubiquinone binding and exchange domains that ultimately trigger and drive proton translocation. We aim to contribute to a comprehensive understanding of redox-linked proton translocation by complex I. In future work we will improve structural resolution, explore different conformational states, and study complex I from the perspective of structurally and functionally related transport proteins.

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Figure 1. Electrons are transferred from the NADH oxidation site to the ubiquinone reduction site via a chain of seven iron-sulfur clusters. Selected residues in the vicinity of FeS cluster N2 that were shown to be critical for ubiquinone reduction are displayed in stick representation (green). The membrane arm comprises three subunits with discontinuous helices (ND5, marine; ND4, cyan; ND2, pink) that show homology to Mrp type cation proton antiporter subunits. In each subunit a potential proton translocation pathway (black arrow) was identified. Residues constituting a putative forth proton pathway (dashed arrow) were found in subunits ND2 and ND4L. In the center of the membrane arm a series of protonable residues (basic, blue; acidic, red) extends from subunit ND5 to subunit ND1 and terminates below the ubiquinone reduction site with a loop comprising a cluster of highly conserved acidic residues. Conformational changes linked to the redox chemistry of ubiquinone are proposed to induce an electric pulse that ultimately triggers proton translocation events in the membrane arm.

 

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Publications

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Kmita K, Wirth C, Warnau J, Guerrero-Castillo S, Hunte C, Hummer G, Kaila VRI, Zwicker K, Brandt U, Zickermann V (2015) The accessory NUMM (NDUFS6) subunit harbors a zinc binding site and is essential for biogenesis of mitochondrial complex I. Proc Natl Acad Sci USA 112, 5685-90.

 

Zickermann V, Wirth C, Nasiri H, Siegmund K, Schwalbe H, Hunte C, Brandt U (2015) Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I. Science 347, 44-49.

 

Angerer H, Radermacher M, Mankowska M, Steger M, Zwicker K, Heide H, Wittig I, Brandt U, Zickermann V (2014) The LYR protein subunit NB4M/NDUFA6 of mitochondrial complex I anchors an acyl carrier protein and is essential for catalytic activity. Proc Natl Acad Sci USA 111, 5207-12.

 

Angerer H, Zwicker K, Wumaier Z, Sokolova L, Heide H, Steger M, Kaiser S, Nubel E, Brutschy B, Radermacher M, Brandt U, Zickermann V (2011) A scaffold of accessory subunits links the peripheral arm and the distal proton pumping module of mitochondrial complex I. Biochem J 437, 279-288.

 

Hunte C, Zickermann V, Brandt U (2010) Functional modules and structural basis of conformational coupling in mitochondrial complex I. Science 329, 448-451.

 

Radermacher M, Ruiz T, Clason T, Benjamin S, Brandt U, Zickermann V (2006) The three-dimensional structure of complex I from Yarrowia lipolytica: A highly dynamic enzyme. J Struct Biol 154, 269-279.

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