F1Fo-ATP synthases produce the universal chemical energy source adenosine triphosphate (ATP) in all living organisms. They convert the energy stored in an electro-chemical gradient of protons (H+) or sodium ions (Na+) into ATP and operate by a unique rotary mechanism. The enzyme consists of the water-soluble F1 and the membrane-embedded Fo complex. The Fo and F1 complexes each represent a molecular motor, which are able to exchange energy by a rotational coupling mechanism. The F1 complex with the three catalytic sites on the three β-subunits is connected via the γ and ε subunits (central stalk) to the membrane-embedded c-oligomer of the Fo complex, and via the outer (or peripheral) stalk δ and b2 subunits to subunit a. Mechanistically the enzyme can be divided into the rotor, which consists of subunits γεcn (n = 8, 10–15), and the stator (assembled from subunits ab2α3β3δ). The ion gradient is utilized to generate torque of the machine’s rotor part against the stator part. This rotation induces conformational changes in the catalytic sites which are instrumental for ATP synthesis. During this process, the ions pass by the Fo complex, causing the rotor to rotate. Rotation is mechanically transduced into the F1 headpiece (α3β3) by the inherently asymmetric γ-subunit and causes conformational changes within each of the three β-subunits, which are in three different conformations at any point in time. This process finally leads to the formation (and release) of ATP from ADP and Pi and in sum, this molecular machine converts electrical (ion gradient) to mechanical (rotor) to chemical (ATP) energy. The enzyme is also able to operate in the opposite direction, to act as an uphill ion pump using the energy released by the hydrolysis of ATP, similar to the V-type ATPases
Our work is focused on the understanding of how this molecular machine works in a biological cell. In particular we are interested in the structure of the membrane-embedded Fo motor, which includes the rotor rings and their neighboring static subunits. We aim to understand how a transmembrane ion motif force causes rotation of the Fo rotor against the stator subunits. The affinity and selectivity of the rotor rings with the coupling ions (Na+ or H+) and their delicate interplay with the stator subunits during ion translocation plays an important role in this process. Beside a detailed biochemical analysis of the enzyme (and enzyme’s parts), we use structural methods such as X-ray crystallography, electron microscopy and atomic force microscopy. They allow a view on the enzyme on different levels of resolution, including atomic details. The adaptation of this enzyme to various bioenergetic challenges in different micro-environments is manifested in the enzyme’s structure and function. Therefore, we are engineering the ATP synthase to our particular needs for the structural and functional investigations. Finally, we are also investigating the ATP synthase as a potential new drug target in the fight against infection diseases.
Preiss L, Langer JD, Yildiz Ö, Eckhardt-Strelau L, Guillemont EG, Koul A, Meier T. Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci Adv, 1: e1500106 (2015).
Leone V, Pogoryelov D, Meier T, Faraldo-Gómez JD. On the principle of ion selectivity in Na+/H+-coupled membrane proteins: Experimental and theoretical studies of an ATP synthase rotor. Proc Natl Acad Sci USA, 112: E1057-1066 (2015).
Matthies D, Zhou W, Klyszejko AL, Anselmi C, Yildiz Ö, Brandt K, Müller V, Faraldo-Gómez JD, Meier T. High-resolution structure and mechanism of an F/V-hybrid rotor ring in a Na+-coupled ATP synthase. Nat Commun, 5, 5286 (2014).
Preiss L, Langer JD, Hicks DB, Liu J, Yildiz Ö, Krulwich TA, Meier T. The c-ring ion-binding site of the ATP synthase from Bacillus pseudofirmus OF4 is adapted to alkaliphilic lifestyle. Mol Microbiol, 92 (2014).
Schulz S, Iglesias-Cans M, Krah A, Yildiz Ö, Leone V, Matthies D, Cook GM, Faraldo-Gómez JD, Meier T. A new type of Na+-driven ATP synthase membrane rotor with a two-carboxylate ion-coupling motif. PLoS Biology, 11, e1001596 (2013).
Preiss L, Klyszejko AL, Hicks DB, Liu J, Fackelmayer OJ, Yildiz Ö, Krulwich TA, Meier T. The c-ring stoichiometry of ATP synthase is adapted to cell physiological requirements of alkaliphilic Bacilllus pseudofirmus OF4. Proc Natl Acad Sci USA, 110, 7874-7879 (2013).
Meier T, Pogoryelov D. ATP synthase structure and function. Encyclopedia of Biophysics (Editor: Roberts GCK). Springer (2013).
Halang P, Leptihn S, Meier T, Vorburger T, Steuber J. The function of the Na+-driven flagellum of Vibrio cholerae is determined by osmolality and pH. J Bacteriol, 95, 4888-4899.
Hakulinen J, Klyszejko AL, Hoffmann J, Eckhardt-Strelau L, Brutschy B, Vonck J, Meier T. A structural study on the architecture of the bacterial ATP synthase Fo motor. Proc Natl Acad Sci USA, 109, E2050-2056 (2012).
Pogoryelov D, Klyszejko AL, Krasnoselska G, Heller E-M, Leone V, Langer JD, Vonck J, Muller DJ, Faraldo-Gómez JD, Meier T. Engineering rotor ring stoichiometries in the ATP synthase. Proc Natl Acad Sci USA 109, E1599-1608 (2012).
Symersky J, Pagadala V, Osowski D, Krah A, Meier T, Faraldo-Gómez JD, Mueller DM. Structure of the proton pore c10 ring of the yeast mitochondrial ATP synthase in the open conformation. Nat Struct Mol Biol 19, 485-491 (2012).
Hammann E, Zappe A, Keis S, Ernst S, Matthies D, Meier T, Cook GM, Börsch M. Step size of the rotary proton motor in single FoF1-ATP synthase from a thermoalkaliphilic bacterium by DCO-ALEX FRET. SPIE proceedings, 8228, 82280A-15 (2012).
Meier T, Faraldo-Gómez JD and Börsch M. ATP synthase: A paradigmatic molecular machine. Molecular Machines in Biology (Editor: Frank J), Cambridge University Press (2011).
Matthies D, Haberstock S, Joos F, Dötsch V, Vonck J, Bernhard F and Meier T. Cell-free expression and assembly of ATP synthase. J Mol Biol 413, 593-603 (2011).
McMillan DG, Ferguson SA, Dey D, Schröder K, Aung HL, Carbone V, Attwood GT, Ronimus RS, Meier T, Janssen PH, Cook GM. A1Ao-ATP synthase of Methanobrevibacter ruminantium couples sodium ions for ATP synthesis under physiological conditions. J Biol Chem (2011).
Kalamorz F, Keis S, McMillan, DG Olsson K, Stanton JA, Stockwell P, Black MA, Klingeman DM, Land ML, Han CS, Martin SL, Becher SA, Peddie CJ, Morgan HW, Matthies D, Preiss L, Meier T, Brown SD and Cook GM. Draft genome sequence of the thermoalkaliphilic Caldalkalibacillus thermarum strain TA2.A1. J Bacteriol, 193, 4290-4291 (2011).
Liu J, Fackelmayer OJ, Hicks DB, Preiss L, Meier T, Sobie, EA and Krulwich TA. Mutations in a helix-1 motif of the ATP synthase c-subunit of Bacillus pseudofirmus OF4 cause functional deficits and changes in the c-ring stability and mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biochemistry, 50, 5497-5506 (2011).
Pogoryelov D, Krah A, Langer JD, Yildiz Ö, Faraldo-Gómez JD and Meier T. Microscopic rotary mechanism of ion translocation in the Fo complex of ATP synthases. Nat Chem Biol, 6, 891-899 (2010).
Hoffmann J, Sokolova L, Preiss L, Hicks DB, Krulwich TA, Morgner N, Wittig I, Schägger H, Meier T and Brutschy B. ATP synthases: cellular nanomotors characterized by LILBID mass spectrometry. Phys Chem Chem Phys, 12, 13375-13382 (2010).
Preiss L, Yildiz Ö, Hicks DB, Krulwich TA and Meier T. A new type of proton coordination in an F1Fo-ATP synthase rotor ring. PLoS Biol, 8, e1000443 (2010).
Krah A, Pogoryelov D, Langer JD, Bond PJ, Meier T and Faraldo-Gómez JD. Structural and energetic basis for H+ versus Na+ binding selectivity in ATP synthase Fo rotors. Biochim Biophys Acta, 1797, 763-772 (2010).
Krah A, Pogoryelov D, Meier T and Faraldo-Gómez JD. On the structure of the proton-binding site in the Fo rotor of chloroplast ATP synthases. J Mol Biol, 395, 20-27 (2010).
Matthies D, Preiss L, Klyszejko AL, Müller DJ, Cook GM, Vonck J and Meier T. The c13 ring from a thermoalkaliphilic ATP synthase reveals an extended diameter due to a special structural region. J Mol Biol 388 611-618 (2009).
Meier T, Krah A, Bond PJ, Pogoryelov D, Diederichs K, Faraldo-Gómez JD. Complete ion-coordination structure in the rotor ring of Na+-dependent F-ATP synthases. J Mol Biol 391 498-507 (2009).
Pogoryelov D, Yildiz Ö, Faraldo-Gómez JD and Meier T. High-resolution structure of the rotor ring of a proton-dependent ATP synthase. Nat Struct Mol Biol 16 1068-1073 (2009).
Fritz M, Klyszejko AL, Morgner N, Vonck J, Brutschy B, Müller, DJ, Meier T and Müller V. An intermediate step in the evolution of ATPases - a hybrid Fo-Vo rotor in a bacterial Na+ F1Fo-ATP synthase. FEBS J 275 1999-2007 (2008).
Morgner N, Hoffmann J, Barth HD, Meier T and Brutschy B. LILBID-mass spectrometry applied to the mass analysis of RNA polymerase II and an F1Fo-ATP synthase. Int J Mass Spectrom 277 309-313 (2008).
Pogoryelov D, Nikolaev Y, Schlattner U, Pervushin K, Dimroth P and Meier T. Probing the rotor subunit interface of the ATP synthase from Ilyobacter tartaricus. FEBS J 275 4850-4862 (2008).
Meier T, Morgner N, Matthies D, Pogoryelov D, Keis S, Cook, GM, Dimroth P and Brutschy B. A tridecameric c-ring of the adenosine triphosphate (ATP) synthase from the thermoalkaliphilic Bacillus sp. strain TA2.A1 facilitates ATP synthesis at low electrochemical proton potential. Mol Microbiol 65 1181-1192 (2007).
Pogoryelov D, Reichen C, Klyszejko AL, Brunisholz R, Müller DJ, Dimroth P and Meier T. The oligomeric state of c-rings from cyanobacterial F-ATP synthases varies from 13 to 15. J Bacteriol 189 5895-5902 (2007).
Dimroth P, von Ballmoos C and Meier T. Catalytic and mechanical cycles in F-ATP synthases. EMBO Rep 7 276-282 (2006).
Meier T, Ferguson SA, Cook GM, Dimroth P and Vonck J. Structural investigations of the membrane-embedded rotor ring of the F-ATPase from Clostridium paradoxum. J Bacteriol 188 7759-7764 (2006).
Meier T, Polzer P, Diederichs K, Welte W and Dimroth P. Structure of the rotor ring of F-type Na+-ATPase from Ilyobacter tartaricus. Science 308 659-662 (2005).
Meier T, Yu J, Raschle T, Henzen F, Dimroth P and Müller DJ. Structural evidence for a constant c11 ring stoichiometry in the sodium F-ATP synthase. FEBS J 272 5474-5483 (2005).
Pogoryelov D, Yu J, Meier T, Vonck J, Dimroth P and Müller DJ. The c15 ring of the Spirulina platensis F-ATP synthase: F1/Fo symmetry mismatch is not obligatory. EMBO Rep 6 1040-1044 (2005).
Dimroth P, von Ballmoos C, Meier T and Kaim G. Electrical power fuels rotary ATP synthase. Structure 11 1469-1473 (2003).
Meier T, Matthey U, von Ballmoos C, Vonck, J, Krug von Nidda T, Kühlbrandt W and Dimroth, P. Evidence for structural integrity in the undecameric c-rings isolated from sodium ATP synthases. J Mol Biol 325 389-397 (2003).
Müller DJ, Engel A, Matthey U, Meier T, Dimroth P and Suda K. Observing membrane protein diffusion at subnanometer resolution. J Mol Biol 327 925-930 (2003).
von Ballmoos, C, Meier T and Dimroth P. Membrane-embedded location of Na+ or H+ binding sites on the rotor ring of F1Fo ATP synthases. Eur J Biochem 269 5581-5589 (2002).
Meier T, von Ballmoos C, Neumann S and Kaim G. DNA sequence of the atp-operon encoding the sodium dependent F1Fo ATP synthase from Ilyobacter tartaricus. Biochim Biophys Acta 1625 221-226 (2002).
Meier T and Dimroth P. Intersubunit bridging by sodium ions as rationale for the unusual stability of the turbines of Na+-F1Fo ATP synthases. EMBO Rep 3 1094-1098 (2002).
Vonck J, Krug von Nidda T, Meier T, Matthey U, Mills DJ, Kühlbrandt W and Dimroth P. Molecular architecture of the undecameric rotor of a bacterial Na+-ATP synthase. J Mol Biol 321 307-316 (2002).
Meier T, Matthey U, Henzen F, Dimroth P and Müller DJ. The central plug in the reconstituted undecameric c cylinder of a bacterial ATP synthase consists of phospholipids. FEBS Lett 505 353-356 (2001).
Müller DJ, Dencher NA, Meier T, Dimroth P, Suda K, Stahlberg H, Engel A, Seelert H and Matthey U. ATP synthase: constrained stoichiometry of the transmembrane rotor. FEBS Lett 504 219-222 (2001).
Stahlberg H, Müller DJ, Suda K, Fotiadis D, Engel A, Meier T, Matthey U and Dimroth P. Bacterial Na+-ATP synthase has an undecameric rotor. EMBO Rep, 2 229-233 (2001).
Prof. Dr. Thomas Meier
Department of Structural Biology
Tel.: +49 (0) 69 6303-3038
Fax: +49 (0) 69 6303-3002
Forschungsgruppen und Projektsleiter