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Stimulation of Na+,K+-ATPase Activity as a Possible Driving Force in Cholesterol Evolution

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Abstract

Cholesterol is exclusively produced by animals and is present in the plasma membrane of all animal cells. In contrast, the membranes of fungi and plants contain other sterols. To explain the exclusive preference of animal cells for cholesterol, we propose that cholesterol may have evolved to optimize the activity of a crucial protein found in the plasma membrane of all multicellular animals, namely the Na+,K+-ATPase. To test this hypothesis, mirror tree and phylogenetic distribution analyses have been conducted of the Na+,K+-ATPase and 3β-hydroxysterol Δ24-reductase (DHCR24), the last enzyme in the Bloch cholesterol biosynthetic pathway. The results obtained support the hypothesis of a co-evolution of the Na+,K+-ATPase and DHCR24. The evolutionary correlation between DHCR24 and the Na+,K+-ATPase was found to be stronger than between DHCR24 and any other membrane protein investigated. The results obtained, thus, also support the hypothesis that cholesterol evolved together with the Na+,K+-ATPase in multicellular animals to support Na+,K+-ATPase activity.

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References

  • Autzen HE, Siuda I, Sonntag Y, Nissen P, Møller JV, Thøgersen L (2015) Regulation of the Ca2+-ATPase by cholesterol: a specific or non-specific effect? Mol Membr Biol 32:75–87

    Article  CAS  PubMed  Google Scholar 

  • Bloom M, Mouritsen OG (1988) The evolution of membranes. Can J Chem 66:706–712

    Article  CAS  Google Scholar 

  • Brown AJ (2004) Of cholesterol-free mice and men. Curr Opin Lipidol 15:373–375

    Article  CAS  PubMed  Google Scholar 

  • Cavalier-Smith T (1975) The origin of nuclei and of eukaryotic cells. Nature 256:463–468

    Article  Google Scholar 

  • Chen L-L, Wang G-Z, Zhang H-Y (2007) Sterol biosynthesis and prokaryotes-to-eukaryotes evolution. Biochem Biophys Res Commun 363:885–888

    Article  CAS  PubMed  Google Scholar 

  • Cornelius F (2001) Modulation of Na,K-ATPase and Na-ATPase activity by phospholipids and cholesterol. I. Steady-state kinetics. Biochemistry 40:8842–8851

    Article  CAS  PubMed  Google Scholar 

  • Cornelius F, Habeck M, Kanai R, Toyoshima C, Karlish SJD (2015) General and specific lipid-protein interactions in Na,K-ATPase. Biochim Biophys Acta Biomembr 1848:1729–1743

    Article  CAS  Google Scholar 

  • Cournia Z, Ullmann GM, Smith JC (2007) Differential effects of cholesterol, ergosterol and lanosterol on a dipalmitoyl phosphatidylcholine membrane: a molecular dynamics study. J Phys Chem B 111:1786–1801

    Article  CAS  PubMed  Google Scholar 

  • De Juan D, Pazos F, Valencia A (2013) Emerging methods in protein co-evolution. Nat Rev Genet 14:249–261

    Article  PubMed  Google Scholar 

  • Felsenstein J (1985) Phylogenies and the comparative method. Am Nat 125:1–15

    Article  Google Scholar 

  • Fernández C, Martin M, Gómez-Coronado D, Lasunción MA (2005) Effects of distal cholesterol biosynthesis inhibitors on cell proliferation and cell cycle progression. J Lipid Res 46:920–929

    Article  PubMed  Google Scholar 

  • Galea AM, Brown AJ (2009) Special relationship between sterols and oxygen: were sterols an adaptation to aerobic life? Free Rad Biol Med 47:880–889

    Article  CAS  PubMed  Google Scholar 

  • Haines TH (2001) Do sterols reduce proton and sodium leaks through lipid bilayers? Prog Lipid Res 40:299–324

    Article  CAS  PubMed  Google Scholar 

  • Henriksen J, Rowat AC, Brief E, Hsueh YW, Thewalt JL, Zuckermann MJ, Ipsen JH (2006) Universal behaviour of membranes with sterols. Biophys J 90:1639–1649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henriksen C, Kjaer-Sorensen K, Einholm AP, Madsen LB, Momeni J, Bendixen C, Oxvig C, Vilsen B, Larsen K (2013) Molecular cloning and characterization of porcine Na+/K+-ATPase isoforms α1, α2, α3 and the ATP1A3 protomer. PLoS One 8:e79127

    Article  PubMed  PubMed Central  Google Scholar 

  • Kanai R, Ogawa H, Vilsen B, Cornelius F, Toyoshima C (2013) Crystal structure of a Na+-bound Na+,K+-ATPase preceding the E1P state. Nature 502:201–206

    Article  CAS  PubMed  Google Scholar 

  • Kidder GM, Watson AJ (2005) Roles of Na,K-ATPase in early development and trophectoderm differentiation. Sem Nephrol 25:352–355

    Article  CAS  Google Scholar 

  • Lanfear R, Welch JJ, Bromham L (2010) Watching the clock: studying variation in rates of molecular evolution between species. Trends Ecol Evol 25:495–503

    Article  PubMed  Google Scholar 

  • Laursen M, Yatime L, Nissen P, Fedosova NU (2013) Crystal structure of the high-affinity Na+,K+-ATPase-ouabain complex with Mg2 + bound in the cation binding site. Proc Natl Acad Sci USA 110:10958–10963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitsche MA, McDonald JG, Hobbs HH, Cohen JC (2015) Flux analysis of cholesterol biosynthesis in vivo reveals multiple tissue and cell-type specific pathways. eLife 4:e07999

    Article  PubMed  Google Scholar 

  • Mouritsen OG, Zuckermann MJ (2004) What’s so special about cholesterol. Lipids 39:1101–1113

    Article  CAS  PubMed  Google Scholar 

  • Nes WR (1974) Role of sterols in membranes. Lipids 9:596–612

    Article  CAS  PubMed  Google Scholar 

  • Nyblom M, Poulsen H, Gourdon P, Reinhard L, Andersson M, Lindahl E, Fedosova N, Nissen P (2013) Crystal structure of Na+,K+-ATPase in the Na+-bound state. Science 342:123–127

    Article  CAS  PubMed  Google Scholar 

  • Ochoa D, Pazos F (2010) Studying the co-evolution of protein families with the Mirrortree web server. Bioinformatics 26:1370–1371

    Article  CAS  PubMed  Google Scholar 

  • Ochoa D, Juan D, Valencia A, Pazos F (2015) Detection of significant protein co-evolution. Bioinformatics 31:2166–2173

    Article  PubMed  Google Scholar 

  • Pazos F, Valencia A (2001) Similarity of phylogenetic trees as indicator of protein-protein interactions. Protein Eng 14:609–614

    Article  CAS  PubMed  Google Scholar 

  • Rossier BC, Baker ME, Studer RA (2015) Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. Physiol Rev 95:297–340

    Article  PubMed  Google Scholar 

  • Sáez AG, Lozano E, Zaldívar-Riverón A (2009) Evolutionary history of Na,K-ATPases and their osmoregulatory role. Genetica 136:479–490

    Article  PubMed  Google Scholar 

  • Sagan L (1967) On the origin of mitosing cells. J Theor Biol 14:255–274

    Article  CAS  PubMed  Google Scholar 

  • Schoenheimer R, Breusch F (1933) Synthesis and destruction of cholesterol in the organism. J Biol Chem 103:439–448

    CAS  Google Scholar 

  • Shinoda T, Ogawa H, Cornelius F, Toyoshima C (2009) Crystal structure of the sodium-potassium pump at 2.4 Å resolution. Nature 459:446–450

    Article  CAS  PubMed  Google Scholar 

  • Starke-Peterkovic T, Turner N, Vitha MF, Waller MP, Hibbs DE, Clarke RJ (2006) Cholesterol effect on the dipole potential of lipid membranes. Biophys J 90:4060–4070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo G (1974) Dual mechanism of action of cholesterol on membrane permeability. Nature 252:47–48

    Article  CAS  PubMed  Google Scholar 

  • Tulenko TN, Boeze-Battaglia K, Mason PR, Tint GS, Steiner RD, Connor WE, Labelle EF (2005) A membrane defect in the pathogenesis of the Smith-Lemli-Opitz syndrome. J Lipid Res 47:134–143

    Article  PubMed  Google Scholar 

  • Van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9:112–124

    Article  PubMed  PubMed Central  Google Scholar 

  • Waterham HR, Koster J, Romeijn GJ, Hennekam RCM, Vreken P, Andersson HC, FitzPatrick DR, Kelley RI, Wanders RJA (2001) Mutations in the 3β-hydroxysterol Δ24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am J Hum Genet 69:685–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wechsler A, Brafman A, Shafir M, Heverin M, Gottlieb H, Damari G, Gozlan-Kelner S, Spivak I, Moshkin O, Fridman E, Becker Y, Skaliter R, Einat P, Faerman A, Björkhem I, Feinstein E (2003) Generation of viable cholesterol-free mice. Science 302:2087

    Article  CAS  PubMed  Google Scholar 

  • Yeagle PL (1985) Cholesterol and the cell membrane. Biochim Biophys Acta 822:267–287

    Article  CAS  PubMed  Google Scholar 

  • Yeagle PL (2014) Non-covalent binding of membrane lipids to membrane proteins. Biochim Biophys Acta 1838:1548–1559

    Article  CAS  PubMed  Google Scholar 

  • Yeagle PL, Young J, Rice D (1988) Effects of cholesterol on (Na+,K+)-ATPase ATP hydrolysing activity in bovine kidney. Biochemistry 27:6449–6452

    Article  CAS  PubMed  Google Scholar 

  • Zerenturk EJ, Sharpe LJ, Ikonen E, Brown AJ (2013) Desmosterol and DHCR24: unexpected new directions for a terminal step in cholesterol synthesis. Prog Lipid Res 52:666–680

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors acknowledge helpful discussions with Prof. Ole Mouritsen, Assoc. Prof. Simon Ho, Assoc. Prof. Neville Firth, Prof. Andrew Brown and Prof. Philip Kuchel. R.J.C acknowledges, with gratitude, the financial support from the Australian Research Council (Discovery Grants DP-121003548 and DP-150101112).

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Authors and Affiliations

  1. School of Chemistry, University of Sydney, Sydney, NSW, 2006, Australia

    Nicholas Lambropoulos, Alvaro Garcia & Ronald J. Clarke

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  1. Nicholas Lambropoulos
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  2. Alvaro Garcia
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  3. Ronald J. Clarke
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Correspondence to Ronald J. Clarke.

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Lambropoulos, N., Garcia, A. & Clarke, R.J. Stimulation of Na+,K+-ATPase Activity as a Possible Driving Force in Cholesterol Evolution. J Membrane Biol 249, 251–259 (2016). https://doi.org/10.1007/s00232-015-9864-z

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  • DOI: https://doi.org/10.1007/s00232-015-9864-z

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