Skip to main content
SpringerLink
Log in

ATP synthase FOF1 structure, function, and structure-based drug design

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

ATP synthases are unique rotatory molecular machines that supply biochemical reactions with adenosine triphosphate (ATP)—the universal “currency”, which cells use for synthesis of vital molecules and sustaining life. ATP synthases of F-type (FOF1) are found embedded in bacterial cellular membrane, in thylakoid membranes of chloroplasts, and in mitochondrial inner membranes in eukaryotes. The main functions of ATP synthases are control of the ATP synthesis and transmembrane potential. Although the key subunits of the enzyme remain highly conserved, subunit composition and structural organization of ATP synthases and their assemblies are significantly different. In addition, there are hypotheses that the enzyme might be involved in the formation of the mitochondrial permeability transition pore and play a role in regulation of the cell death processes. Dysfunctions of this enzyme lead to numerous severe disorders with high fatality levels. In our review, we focus on FOF1-structure-based approach towards development of new therapies by using FOF1 structural features inherited by the representatives of this enzyme family from different taxonomy groups. We analyzed and systematized the most relevant information about the structural organization of FOF1 to discuss how this approach might help in the development of new therapies targeting ATP synthases and design tools for cellular bioenergetics control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

The figure is reprinted from [4]

Fig. 2

The figure was slightly modified from ref. [4]

Fig. 3
Fig. 4

The figure was taken from ref. [4]

Fig. 5
Fig. 6

The figure is from [77]

Fig. 7
Fig. 8
Fig. 9
Fig. 10

The figure was reprinted from ref. [4] with modifications

Fig. 11

The figure was reprinted from ref. [4] with modifications

Fig. 12

The figure was reprinted from ref. [4]

Fig. 13

The figure was reprinted from ref. [4]

Fig. 14

The figure was modified from [25]

Fig. 15

Similar content being viewed by others

Availability of data and materials

Not applicable.

References

  1. Walker JE (2013) The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans 41:1–16

    CAS  PubMed  Google Scholar 

  2. Junge W, Nelson N (2015) ATP synthase. Annu Rev Biochem 84:631–657

    CAS  PubMed  Google Scholar 

  3. Hahn A, Vonck J, Mills DJ, Meier T, Kühlbrandt W (2018) Structure, mechanism, and regulation of the chloroplast ATP synthase. Science 360:eaat4318

    PubMed  PubMed Central  Google Scholar 

  4. Vlasov AV (2021) New structural insights in chloroplast F1FO-ATP synthases—RWTH Publications. RWTH Aachen University. https://doi.org/10.18154/RWTH-2021-00849

  5. Kühlbrandt W (2019) Structure and mechanisms of F-Type ATP synthases. Annu Rev Biochem 88:515–549

    PubMed  Google Scholar 

  6. Morales-Rios E, Montgomery MG, Leslie AGW, Walker JE (2015) Structure of ATP synthase from Paracoccus denitrificans determined by X-ray crystallography at 4.0 Å resolution. Proc Natl Acad Sci USA 112:13231–13236

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sobti M et al (2020) Cryo-EM structures provide insight into how E. coli F1Fo ATP synthase accommodates symmetry mismatch. Nat Commun 11:1–10

    Google Scholar 

  8. Daum B, Nicastro D, Austin J, Richard MJ, Kühlbrandt W (2010) Arrangement of photosystem II and ATP synthase in chloroplast membranes of spinach and pea. Plant Cell 22:1299–1312

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Seelert H, Dencher NA (2011) ATP synthase superassemblies in animals and plants: two or more are better. Biochim Biophys Acta Bioenerg 1807:1185–1197

    CAS  Google Scholar 

  10. Mühleip A et al (2021) ATP synthase hexamer assemblies shape cristae of Toxoplasma mitochondria. Nat Commun 12:1–13

    Google Scholar 

  11. Flygaard RK, Mühleip A, Tobiasson V, Amunts A (2020) Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization. Nat Commun 11:1–11

    Google Scholar 

  12. Nuskova H et al (2019) Biochemical thresholds for pathological presentation of ATP synthase deficiencies. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2019.11.033

    Article  PubMed  Google Scholar 

  13. Neupane P, Bhuju S, Thapa N, Bhattarai HK (2019) ATP synthase: structure, function and inhibition. Biomol Concepts 10:1–10

    CAS  PubMed  Google Scholar 

  14. Gerle C (2016) On the structural possibility of pore-forming mitochondrial FoF1 ATP synthase. Biochim Biophys Acta Bioenerg 1857:1191–1196

    CAS  Google Scholar 

  15. Carraro M, Carrer A, Urbani A, Bernardi P (2020) Molecular nature and regulation of the mitochondrial permeability transition pore(s), drug target(s) in cardioprotection. J Mol Cell Cardiol 144:76–86

    CAS  PubMed  Google Scholar 

  16. Walker JE, Carroll J, He J (2020) Reply to Bernardi: the mitochondrial permeability transition pore and the ATP synthase. Proc Natl Acad Sci 117:2745–2746

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Petronilli V, Szabò I, Zoratti M (1989) The inner mitochondrial membrane contains ion-conducting channels similar to those found in bacteria. FEBS Lett 259:137–143

    CAS  PubMed  Google Scholar 

  18. Szabo I, Zoratti M (1991) The giant channel of the inner mitochondrial membrane is inhibited by cyclosporin A. J Biol Chem 266:3376–3379

    CAS  PubMed  Google Scholar 

  19. Szabó I, Zoratti M (1992) The mitochondrial megachannel is the permeability transition pore. J Bioenerg Biomembr 24:111–117

    PubMed  Google Scholar 

  20. Szabo I, Bernardi P, Zoratti M (1992) Modulation of the mitochondrial megachannel by divalent cations and protons. J Biol Chem 267:2940–2946

    CAS  PubMed  Google Scholar 

  21. Kinnally KW, Zorov DYA, Perini S (1991) Calcium modulation of mitochondrial inner membrane channel activity. Biochem Biophys Res Commun 176:1183–1188

    CAS  PubMed  Google Scholar 

  22. Bernardi P et al (1992) Modulation of the mitochondrial permeability transition pore. Effect of protons and divalent cations. J Biol Chem 267:2934–2939

    CAS  PubMed  Google Scholar 

  23. Vlasov AV et al (2019) Unusual features of the c-ring of F1FO ATP synthases. Sci Rep 9:18547

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Preiss L et al (2015) Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci Adv 1:e1500106–e1500106

    PubMed  PubMed Central  Google Scholar 

  25. Guo H et al (2021) Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline. Nature 589:143–147

    CAS  PubMed  Google Scholar 

  26. Grinkova YV, Denisov IG, Sligar SG (2010) Engineering extended membrane scaffold proteins for self-assembly of soluble nanoscale lipid bilayers. Protein Eng Des Sel 23:843–848

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Muñoz-Gómez SA, Wideman JG, Roger AJ, Slamovits CH (2017) The origin of mitochondrial cristae from alphaproteobacteria. Mol Biol Evol 34:943–956

    PubMed  Google Scholar 

  28. Eydt K, Davies KM, Behrendt C, Wittig I, Reichert AS (2017) Cristae architecture is determined by an interplay of the MICOS complex and the F1Fo ATP synthase via Mic27 and Mic10. Microb Cell 4:259–272

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Davies KM, Anselmi C, Wittig I, Faraldo-Gómez JD, Kühlbrandt W (2012) Structure of the yeast F1Fo-ATP synthase dimer and its role in shaping the mitochondrial cristae. Proc Natl Acad Sci USA 109:13602–13607

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Schoch CL et al (2020) NCBI taxonomy: a comprehensive update on curation, resources and tools. Database 2020: baaa062. PubMed: 32761142 PMC: PMC7408187

  31. Sobti M et al (2016) Cryo-EM structures of the autoinhibited E. coli ATP synthase in three rotational states. Elife 5:e21598

    PubMed  PubMed Central  Google Scholar 

  32. Guo H, Suzuki T, Rubinstein JL (2019) Structure of a bacterial ATP synthase. Elife 8:e43128

    PubMed  PubMed Central  Google Scholar 

  33. Guo H, Bueler SA, Rubinstein JL (2017) Atomic model for the dimeric FOregion of mitochondrial ATP synthase. Science 358:936–940

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gu J et al (2019) Cryo-EM structure of the mammalian ATP synthase tetramer bound with inhibitory protein IF1. Science 364:1068–1075

    CAS  PubMed  Google Scholar 

  35. Rexroth S et al (2004) Dimeric H+-ATP synthase in the chloroplast of Chlamydomonas reinhardtii. Biochim Biophys Acta Bioenerg 1658:202–211

    CAS  Google Scholar 

  36. Schwaßmann HJ, Rexroth S, Seelert H, Dencher NA (2007) Metabolism controls dimerization of the chloroplast FoF1 ATP synthase in Chlamydomonas reinhardtii. FEBS Lett 581:1391–1396

    PubMed  Google Scholar 

  37. Murphy BJ et al (2019) Rotary substates of mitochondrial ATP synthase reveal the basis of flexible F1–Fo coupling. Science 364:eaaw9128

    CAS  PubMed  Google Scholar 

  38. Blum TB, Hahn A, Meier T, Davies KM, Kühlbrandt W (2019) Dimers of mitochondrial ATP synthase induce membrane curvature and self-assemble into rows. Proc Natl Acad Sci USA 116:4250–4255

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Mühleip AW, Dewar CE, Schnaufer A, Kühlbrandt W, Davies KM (2017) In situ structure of trypanosomal ATP synthase dimer reveals a unique arrangement of catalytic subunits. Proc Natl Acad Sci 114:992–997

    PubMed  PubMed Central  Google Scholar 

  40. Mühleip A, McComas SE, Amunts A (2019) Structure of a mitochondrial ATP synthase with bound native cardiolipin. Elife 8:e51179

    PubMed  PubMed Central  Google Scholar 

  41. Vlasov AV, Ryzhykau YL, Gordeliy VI, Kuklin AI (2017) Spinach ATP-synthases form dimers in nanodiscs. Small-angle X-ray and neutron scattering investigations. FEBS J 284:87

    Google Scholar 

  42. Yanyushin MF (1993) Subunit structure of ATP synthase from chloroflexus aurantiacus. FEBS Lett 335:85–88

    CAS  PubMed  Google Scholar 

  43. Yanyushin MF (1997) Determination of subunit composition of the F 1 and F 0 moieties of ATP synthase from Chloroflexus aurantiacus. Biochem 62:285–288

    CAS  Google Scholar 

  44. Abrahams JP, Leslie AGW, Lutter R, Walker JE (1994) Structure at 28 Â resolution of F1-ATPase from bovine heart mitochondria. Nature 370:621–628

    CAS  PubMed  Google Scholar 

  45. Stock D, Leslie AGW, Walker JE (1999) Molecular architecture of the rotary motor in ATP synthase. Science 286:1700–1705

    CAS  PubMed  Google Scholar 

  46. Dautant A, Velours J, Giraud MF (2010) Crystal structure of the Mg·ADP-inhibited state of the yeast F 1c10-ATP synthase. J Biol Chem 285:29502–29510

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Watt IN, Montgomery MG, Runswick MJ, Leslie AGW, Walker JE (2010) Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. Proc Natl Acad Sci USA 107:16823–16827

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Giraud MF et al (2012) Rotor architecture in the yeast and bovine F 1-c-ring complexes of F-ATP synthase. J Struct Biol 177:490–497

    CAS  PubMed  Google Scholar 

  49. Morales-Rios E et al (2015) Purification, characterization and crystallization of the F-ATPase from Paracoccus denitrificans. Open Biol 5:150119

    PubMed  PubMed Central  Google Scholar 

  50. Hahn A et al (2016) Structure of a complete ATP synthase dimer reveals the molecular basis of inner mitochondrial membrane morphology. Mol Cell 63:445–456

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Seelert H et al (2000) Proton-powered turbine of a plant motor. Nature 405:418–419

    CAS  PubMed  Google Scholar 

  52. Zhou A et al (2015) Structure and conformational states of the bovine mitochondrial ATP synthase by cryo-EM. Elife 4:e10180

    PubMed  PubMed Central  Google Scholar 

  53. Allegretti M et al (2015) Horizontal membrane-intrinsic α-helices in the stator a-subunit of an F-type ATP synthase. Nature 521:237–240

    CAS  PubMed  Google Scholar 

  54. Vinothkumar KR, Montgomery MG, Liu S, Walker JE (2016) Structure of the mitochondrial ATP synthase from Pichia angusta determined by electron cryo-microscopy. Proc Natl Acad Sci USA 113:12709–12714

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Srivastava AP et al (2018) High-resolution cryo-EM analysis of the yeast ATP synthase in a lipid membrane. Science 360:6389

    Google Scholar 

  56. Mellwig C, Böttcher B (2003) A unique resting position of the ATP-synthase from Chloroplasts*. J Biol Chem 278:18544–18549

    CAS  PubMed  Google Scholar 

  57. Guo H, Bueler SA, Rubinstein JL (2017) Atomic model for the dimeric FO region of mitochondrial ATP synthase. Science 358:936–940

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Allen RD, Schroeder CC, Fok AK (1989) An investigation of mitochondrial inner membranes by rapid-freeze deep-etch techniques. J Cell Biol 108:2233–2240

    CAS  PubMed  Google Scholar 

  59. Nicastro D, Frangakis AS, Typke D, Baumeister W (2000) Cryo-electron tomography of neurospora mitochondria. J Struct Biol 129:48–56

    CAS  PubMed  Google Scholar 

  60. Giraud MF et al (2002) Is there a relationship between the supramolecular organization of the mitochondrial ATP synthase and the formation of cristae? Biochim Biophys Acta Bioenerg 1555:174–180

    CAS  Google Scholar 

  61. Benvenuti M, Mangani S (2007) Crystallization of soluble proteins in vapor diffusion for X-ray crystallography. Nat Protoc 2:1633–1651

    CAS  PubMed  Google Scholar 

  62. Balakrishna AM, Seelert H, Marx S-H, Dencher NA, Grüber G (2014) Crystallographic structure of the turbine C-ring from spinach chloroplast F-ATP synthase. Biosci Rep 34:e00102

    PubMed  PubMed Central  Google Scholar 

  63. Caffrey M, Cherezov V (2009) Crystallizing membrane proteins using lipidic mesophases. Nat Protoc 4:706–731

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Li D, Shah STA, Caffrey M (2013) Host lipid and temperature as important screening variables for crystallizing integral membrane proteins in lipidic mesophases. Trials with diacylglycerol kinase. Cryst Growth Des 13:2846–2857

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Ishchenko A et al (2017) Chemically stable lipids for membrane protein crystallization. Cryst Growth Des 17:3502–3511

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zabara A et al (2018) Design of ultra-swollen lipidic mesophases for the crystallization of membrane proteins with large extracellular domains. Nat Commun 9:1–9

    CAS  Google Scholar 

  67. Johnson DE et al (2012) High-throughput characterization of intrinsic disorder in proteins from the protein structure initiative. J Struct Biol 180:201–215

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Sedzik J, Kirschner DA (1992) Is myelin basic protein crystallizable? Neurochem Res 17:157–166

    CAS  PubMed  Google Scholar 

  69. Harauz G et al (2004) Myelin basic protein-diverse conformational states of an intrinsically unstructured protein and its roles in myelin assembly and multiple sclerosis. Micron 35:503–542

    CAS  PubMed  Google Scholar 

  70. Le Gall T, Romero PR, Cortese MS, Uversky VN, Dunker AK (2007) Intrinsic disorder in the protein data bank. J Biomol Struct Dyn 24:325–341

    PubMed  Google Scholar 

  71. DeForte S, Uversky VN (2016) Resolving the ambiguity: making sense of intrinsic disorder when PDB structures disagree. Protein Sci 25:676–688

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Romero P et al (2000) Sequence complexity of disordered protein. Proteins Struct Funct Bioinform 42:38–48

    Google Scholar 

  73. Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinform 7:208–212

    Google Scholar 

  74. Peng K et al (2005) Optimizing long intrinsic disorder predictors with protein evolutionary information. J Bioinform Comput Biol 3:35–60

    CAS  PubMed  Google Scholar 

  75. Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN (2010) PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 1804:996–1010

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Mészáros B, Erdos G, Dosztányi Z (2018) IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res 46:W329–W337

    PubMed  PubMed Central  Google Scholar 

  77. Mendoza-Hoffmann F, Zarco-Zavala M, Ortega R, García-Trejo JJ (2018) Control of rotation of the F1FO-ATP synthase nanomotor by an inhibitory α-helix from unfolded ε or intrinsically disordered ζ and IF1 proteins. J Bioenerg Biomembr 50:403–424

    CAS  PubMed  Google Scholar 

  78. Yang J-H, Williams D, Kandiah E, Fromme P, Chiu P-L (2020) Structural basis of redox modulation on chloroplast ATP synthase. Commun Biol 3:1–12

    Google Scholar 

  79. Fischer S et al (1994) ATP synthesis catalyzed by the ATP synthase of Escherichia coli reconstituted into liposomes. Eur J Biochem 225:167–172

    CAS  PubMed  Google Scholar 

  80. Poetsch A et al (2003) Characterisation of subunit III and its oligomer from spinach chloroplast ATP synthase. Biochim Biophys Acta Biomembr 1618:59–66

    CAS  Google Scholar 

  81. Suhai T, Dencher NA, Poetsch A, Seelert H (2008) Remarkable stability of the proton translocating F1FO-ATP synthase from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1. Biochim Biophys Acta Biomembr 1778:1131–1140

    CAS  Google Scholar 

  82. Suhai T, Heidrich NG, Dencher NA, Seelert H (2009) Highly sensitive detection of ATPase activity in native gels. Electrophoresis 30:3622–3625

    CAS  PubMed  Google Scholar 

  83. Schmidt G, Gräber P (1985) The rate of ATP synthesis by reconstituted CF0F1 liposomes. Biochim Biophys Acta Bioenerg 808:46–51

    CAS  Google Scholar 

  84. Förster K et al (2010) Proton transport coupled ATP synthesis by the purified yeast H+-ATP synthase in proteoliposomes. Biochim Biophys Acta Bioenerg 1797:1828–1837

    Google Scholar 

  85. Turina P, Samoray D, Gräber P (2003) H+/ATP ratio of proton transport-coupled ATP synthesis and hydrolysis catalysed by CF0F1-liposomes. EMBO J. https://doi.org/10.1093/emboj/cdg073

    Article  PubMed  PubMed Central  Google Scholar 

  86. Groth G, Walker JE (1996) ATP synthase from bovine heart mitochondria: reconstitution into unilamellar phospholipid vesicles of the pure enzyme in a functional state. Biochem J 318:351–357

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Varco-Merth B, Fromme R, Wang M, Fromme P (2008) Crystallization of the c14-rotor of the chloroplast ATP synthase reveals that it contains pigments. Biochim Biophys Acta Bioenerg 1777:605–612

    CAS  Google Scholar 

  88. Grotjohann I, Gräber P (2002) The H+-ATPase from chloroplasts: effect of different reconstitution procedures on ATP synthesis activity and on phosphate dependence of ATP synthesis. Biochim Biophys Acta Bioenerg 1556:208–216

    CAS  Google Scholar 

  89. Pogoryelov D et al (2012) Engineering rotor ring stoichiometries in the ATP synthase. Proc Natl Acad Sci USA 109:E1599–E1608

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Luz AL, Lagido C, Hirschey MD, Meyer JN (2016) In vivo determination of mitochondrial function using luciferase-expressing caenorhabditis elegans: contribution of oxidative phosphorylation, glycolysis, and fatty acid oxidation to toxicant-induced dysfunction. Curr Protoc Toxicol 69:2581–25822

    Google Scholar 

  91. Boerries M et al (2007) Ca2+-dependent interaction of S100A1 with F1-ATPase leads to an increased ATP content in cardiomyocytes. Mol Cell Biol 27:4365–4373

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Drew B, Leeuwenburgh C (2003) Method for measuring ATP production in isolated mitochondria: ATP production in brain and liver mitochondria of Fischer-344 rats with age and caloric restriction. Am J Physiol Regul Integr Comp Physiol 285:1259–1267

    Google Scholar 

  93. Vinkler C, Korenstein R (1982) Characterization of external electric field-driven ATP synthesis in chloroplasts. Proc Natl Acad Sci 79:3183–3187

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Sun T et al (2000) Ralstonia solanacearum elicitor RipX induces defense reaction by suppressing the mitochondrial atpA gene in host plant. Int J Mol Sci 2020:21

    Google Scholar 

  95. Meighen EA (1991) Molecular biology of bacterial bioluminescence. Microbiol Rev 55:123–142

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Nijvipakul S et al (2008) LuxG is a functioning flavin reductase for bacterial luminescence. J Bacteriol 190:1531–1538

    CAS  PubMed  Google Scholar 

  97. Kalyabina VP, Esimbekova EN, Torgashina IG, Kopylova KV, Kratasyuk VA (2019) Principles for construction of bioluminescent enzyme biotests for analysis of complex media. Dokl Biochem Biophys 485:107–110

    CAS  PubMed  Google Scholar 

  98. Zavilgelsky GB, Kotova VY, Mazhul’ MM, Manukhov IV (2002) Role of Hsp70 (DnaK–DnaJ–GrpE) and Hsp100 (ClpA and ClpB) chaperones in refolding and increased thermal stability of bacterial luciferases in Escherichia coli cells. Biochem 67:986–992

    CAS  Google Scholar 

  99. Bernardi P (2020) Mechanisms for Ca2+-dependent permeability transition in mitochondria. Proc Natl Acad Sci USA 117:2743–2744

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Neginskaya MA et al (2019) ATP synthase c-subunit-deficient mitochondria have a small cyclosporine a-sensitive channel, but lack the permeability transition pore. Cell Rep 26:11-17.e2

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Giorgio V et al (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proc Natl Acad Sci 110:5887–5892

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kokoszka JE et al (2004) The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461–465

    CAS  PubMed  PubMed Central  Google Scholar 

  103. He J et al (2017) Persistence of the mitochondrial permeability transition in the absence of subunit c of human ATP synthase. Proc Natl Acad Sci 114:3409–3414

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Alavian KN et al (2014) An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore. Proc Natl Acad Sci 111:10580–10585

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Bernardi P, Di Lisa F (2015) The mitochondrial permeability transition pore: molecular nature and role as a target in cardioprotection. J Mol Cell Cardiol 78:100–106

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhou W, Marinelli F, Nief C, Faraldo-Gómez JD (2017) Atomistic simulations indicate the c-subunit ring of the F1Fo ATP synthase is not the mitochondrial permeability transition pore. Elife 6:e23781

    PubMed  PubMed Central  Google Scholar 

  107. Spikes TE, Montgomery MG, Walker JE (2020) Structure of the dimeric ATP synthase from bovine mitochondria. Proc Natl Acad Sci 117:23519–23526

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Carraro M et al (2014) Channel formation by yeast F-ATP synthase and the role of dimerization in the mitochondrial permeability transition. J Biol Chem 289:15980–15985

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Carraro M et al (2018) High-conductance channel formation in yeast mitochondria is mediated by F-ATP synthase e and g subunits. Cell Physiol Biochem 50:1840–1855

    CAS  PubMed  Google Scholar 

  110. Urbani A et al (2019) Purified F-ATP synthase forms a Ca2+-dependent high-conductance channel matching the mitochondrial permeability transition pore. Nat Commun 10:1–11

    CAS  Google Scholar 

  111. Bonora M et al (2017) Mitochondrial permeability transition involves dissociation of F1FO ATP synthase dimers and C-ring conformation. EMBO Rep 18:1077–1089

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Mnatsakanyan N et al (2019) A mitochondrial megachannel resides in monomeric F1FO ATP synthase. Nat Commun 10:1–11

    CAS  Google Scholar 

  113. Pinke G, Zhou L, Sazanov LA (2020) Cryo-EM structure of the entire mammalian F-type ATP synthase. Nat Struct Mol Biol 27:1077–1085

    CAS  PubMed  Google Scholar 

  114. Amodeo GF et al (2021) C subunit of the ATP synthase is an amyloidogenic calcium dependent channel-forming peptide with possible implications in mitochondrial permeability transition. Sci Rep 11:1–10

    Google Scholar 

  115. Matthies D et al (2014) High-resolution structure and mechanism of an F/V-hybrid rotor ring in a Na+-coupled ATP synthase. Nat Commun 5:5286

    PubMed  Google Scholar 

  116. Meier T, Matthey U, Henzen F, Dimroth P, Müller DJ (2001) The central plug in the reconstituted undecameric c cylinder of a bacterial ATP synthase consists of phospholipids. FEBS Lett 505:353–356

    CAS  PubMed  Google Scholar 

  117. Seelert H, Dencher NA, Müller DJ (2003) Fourteen protomers compose the oligomer III of the proton-rotor in spinach chloroplast ATP synthase. J Mol Biol 333:337–344

    CAS  PubMed  Google Scholar 

  118. Novitskaia O, Buslaev P, Gushchin I (2019) Assembly of spinach chloroplast ATP synthase rotor ring protein–lipid complex. Front Mol Biosci 6:135

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Meier T et al (2009) Complete ion-coordination structure in the rotor ring of Na+-dependent F-ATP synthases. J Mol Biol 391:498–507

    CAS  PubMed  Google Scholar 

  120. Fromme P, Gräber P, Boekema EJ (1987) Isolation and characterization of a supramolecular complex of subunit III of the ATP-synthase from chloroplasts. Zeitschrift fur Naturforsch Sect C J Biosci 42:1239–1245

    CAS  Google Scholar 

  121. Vollmar M, Schlieper D, Winn M, Büchner C, Groth G (2009) Structure of the c14 rotor ring of the proton translocating chloroplast ATP synthase. J Biol Chem 284:18228–18235

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Symersky J et al (2012) Structure of the c10 ring of the yeast mitochondrial ATP synthase in the open conformation. Nat Struct Mol Biol 19:485–491

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Preiss L et al (2014) The c-ring ion binding site of the ATP synthase from Bacillus pseudofirmus OF4 is adapted to alkaliphilic lifestyle. Mol Microbiol 92:973–984

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Pogoryelov D et al (2010) Microscopic rotary mechanism of ion translocation in the Fo complex of ATP synthases. Nat Chem Biol 6:891–899

    CAS  PubMed  Google Scholar 

  125. Spikes TE, Montgomery MG, Walker JE (2021) Interface mobility between monomers in dimeric bovine ATP synthase participates in the ultrastructure of inner mitochondrial membranes. Proc Natl Acad Sci 118

  126. Tacconelli E et al (2018) Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 18:318–327

    PubMed  Google Scholar 

  127. Gao W, Howden BP, Stinear TP (2018) Evolution of virulence in Enterococcus faecium, a hospital-adapted opportunistic pathogen. Curr Opin Microbiol 41:76–82

    PubMed  Google Scholar 

  128. Li Y, Sun F, Zhang W (2019) Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: promising but challenging. Drug Dev Res 80:98–105

    CAS  PubMed  Google Scholar 

  129. Kevric I, Cappel MA, Keeling JH (2015) New world and old world leishmania infections: a practical review. Dermatol Clin 33:579–593

    CAS  PubMed  Google Scholar 

  130. Migchelsen SJ, Büscher P, Hoepelman AIM, Schallig HDFH, Adams ER (2011) Human African trypanosomiasis: a review of non-endemic cases in the past 20 years. Int J Infect Dis 15:e517–e524

    PubMed  Google Scholar 

  131. Young KM et al (2019) Zoonotic Babesia: a scoping review of the global evidence. PLoS One 14:e0226781

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Saadatnia G, Golkar M (2012) A review on human toxoplasmosis. Scand J Infect Dis. https://doi.org/10.3109/00365548.2012.693197

    Article  PubMed  Google Scholar 

  133. Schuster FL, Ramirez-Avila L (2008) Current world status of Balantidium coli. Clin Microbiol Rev 21:626–638

    PubMed  PubMed Central  Google Scholar 

  134. Fayer R, Ungar BLP (1986) Cryptosporidium spp. and Cryptosporidiosis. Microbiol Rev 50:458–483

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Tuteja R (2007) Malaria—an overview. FEBS J 274:4670–4679

    CAS  PubMed  Google Scholar 

  136. Clark C, Espinosa Cantellano M, Bhattacharya A (2000) Entamoeba Histolytica: an overview of the biology of the organism. Amebiasis. https://doi.org/10.1142/9781848160583_0001

    Article  Google Scholar 

  137. El-Dib NA (2017) Entamoeba histolytica: an overview. Curr Trop Med Rep 4:11–20

    Google Scholar 

  138. Visvesvara GS (1983) Giardiasis: an overview. IMJ Ill Med J 164:34–39

    CAS  PubMed  Google Scholar 

  139. Docampo R, Ryan CM, de Miguel N, Johnson PJ (2011) Trichomonas vaginalis: current understanding of host-parasite interactions. Essays Biochem 51:161–175

    Google Scholar 

  140. Jumper J et al (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596:583–589

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Tunyasuvunakool K et al (2021) Highly accurate protein structure prediction for the human proteome. Nature 596:590–596

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Baek M et al (2021) Accurate prediction of protein structures and interactions using a three-track neural network. Science 373:871–876

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Mullard A (2021) What does AlphaFold mean for drug discovery? Nat Rev Drug Discov 20:725–727

    CAS  PubMed  Google Scholar 

  144. Cui Y et al (2020) Recent progress in the use of mitochondrial membrane permeability transition pore in mitochondrial dysfunction-related disease therapies. Mol Cell Biochem 476:493–506

    PubMed  Google Scholar 

Download references

Acknowledgements

AVV greatly acknowledges the Council for Grants of the President of the Russian Federation for state support of young Russian scientists and for state support of leading scientific schools of the Russian Federation (Scholarship of the President of the Russian Federation, Order of the Ministry of Education and Science of the Russian Federation of January 26, 2021 No. 54 on the appointment of a scholarship for 2021-2023). SDO acknowledges funding from the Foundation of Promoting Innovations for financial support in the framework of the program UMNIK. VIG acknowledges funding from Frankfurt: Cluster of Excellence Frankfurt Macromolecular Complexes (to E.B.) by the Max Planck Society (to E.B.) and by the Commissariat à l’Energie Atomique et aux Energies Alternatives (Institut de Biologie Structurale) – Helmholtz-Gemeinschaft Deutscher Forschungszentren (Forschungszentrum Jülich) Special Terms and Conditions 5.1 specific agreement.

Funding

The work is supported by RFBR 19-29-12022. The work is supported by the Ministry of Science and Higher Education of the Russian Federation (075-00337-20-03/FSMG-2020-0003; 075–00958-21–05, project # 730000F.99.1.BV10AA00006).

Author information

Authors and Affiliations

  1. Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, 141700, Dolgoprudny, Russia

    Alexey V. Vlasov, Stepan D. Osipov, Nikolay A. Bondarev, Vladimir N. Uversky, Valentin I. Borshchevskiy, Ilya V. Manukhov, Andrey V. Rogachev, Anastasiia D. Vlasova, Nikolay S. Ilyinsky, Alexandr I. Kuklin, Norbert A. Dencher & Valentin I. Gordeliy

  2. Joint Institute for Nuclear Research, 141980, Dubna, Russia

    Alexey V. Vlasov, Andrey V. Rogachev & Alexandr I. Kuklin

  3. Department of Molecular Medicine and Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Vladimir N. Uversky

  4. Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52425, Jülich, Germany

    Valentin I. Borshchevskiy & Valentin I. Gordeliy

  5. JuStruct: Jülich Center for Structural Biology, Forschungszentrum Jülich, 52428, Jülich, Germany

    Valentin I. Borshchevskiy & Valentin I. Gordeliy

  6. Institute of Basic Biological Problems, Russian Academy of Sciences, 142290, Pushchino, Moscow region, Russia

    Mikhail F. Yanyushin

  7. Physical Biochemistry, Department Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Straße 4, 64287, Darmstadt, Germany

    Norbert A. Dencher

  8. Institut de Biologie Structurale Jean-Pierre Ebel, Université Grenoble Alpes-Commissariat à l’Energie Atomique et aux Energies Alternatives-CNRS, 38027, Grenoble, France

    Valentin I. Gordeliy

Authors
  1. Alexey V. Vlasov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stepan D. Osipov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nikolay A. Bondarev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vladimir N. Uversky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Valentin I. Borshchevskiy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mikhail F. Yanyushin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ilya V. Manukhov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrey V. Rogachev
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anastasiia D. Vlasova
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nikolay S. Ilyinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alexandr I. Kuklin
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Norbert A. Dencher
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Valentin I. Gordeliy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AVV designed, conceived and wrote the manuscript. SDO strongly contributed to the section “ATP synthases as potential therapeutic targets”, edited the text of the manuscript. NAB strongly contributed to the section “Mitochondrial permeability transition pore (mPTP)”. VNU strongly contributed to the section “Intrinsically disordered regions in ATP synthases”, contributed to all sections and edited the text of the manuscript. VIB contributed to the section “Outlook”, edited the text of the manuscript. MFY contributed to the section “Similarity and diversity of ATP synthases”. IVM contributed to the section “Validation of ATP synthase functionality”, edited the text of the manuscript. AVR organized funding acquisition, edited the text of the manuscript. ADV contributed to the section “Small-molecule cofactors of the c-ring”, edited the text of the manuscript. NSI contributed to the section “Intrinsically disordered regions in ATP synthases”, edited the text of the manuscript. AIK contributed to the section “High-resolution structural studies”. NAD contributed to all sections and edited the text of the manuscript. VIG supervised the project, strongly contributed to all sections and edited the text of the manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Valentin I. Gordeliy.

Ethics declarations

Conflict of interests

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vlasov, A.V., Osipov, S.D., Bondarev, N.A. et al. ATP synthase FOF1 structure, function, and structure-based drug design. Cell. Mol. Life Sci. 79, 179 (2022). https://doi.org/10.1007/s00018-022-04153-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-022-04153-0

Keywords

Search

Navigation