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The Driving Force of Alpha-Synuclein Insertion and Amyloid Channel Formation in the Plasma Membrane of Neural Cells: Key Role of Ganglioside- and Cholesterol-Binding Domains

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Lipid-mediated Protein Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 991))

Abstract

Alpha-synuclein is an amyloidogenic protein expressed in brain and involved in Parkinson’s disease. It is an intrinsically disordered protein that folds into an alpha-helix rich structure upon binding to membrane lipids. Helical alpha-synuclein can penetrate the membrane and form oligomeric ion channels, thereby eliciting important perturbations of calcium fluxes. The study of alpha-synuclein/lipid interactions had shed some light on the molecular mechanisms controlling the targeting and functional insertion of alpha-synuclein in neural membranes. The protein first interacts with a cell surface glycosphingolipid (ganglioside GM3 in astrocytes or GM1 in neurons). This induces the folding of an alpha-helical domain containing a tilted peptide (67–78) that displays a high affinity for cholesterol. The driving force of the insertion process is the formation of a transient OH-Pi hydrogen bond between the ganglioside and the aromatic ring of the alpha-synuclein residue Tyr-39. The higher polarity of Tyr-39 vs. the lipid bilayer forces the protein to cross the membrane, allowing the tilted peptide to reach cholesterol. The tilted geometry of the cholesterol/alpha-synuclein complex facilitates the formation of an oligomeric channel. Interestingly, this functional cooperation between glycosphingolipids and cholesterol presents a striking analogy with virus fusion mechanisms.

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References

  1. Li J, Uversky V, Fink AL (2001) Effect of familial Parkinson’s disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. Biochemistry 40:11604–11613

    Article  PubMed  CAS  Google Scholar 

  2. Stöckl M, Fischer P, Wanker E et al (2008) Alpha-synuclein selectively binds to anionic phospholipids embedded in liquid-disordered domains. J Mol Biol 375:1394–1404

    Article  PubMed  Google Scholar 

  3. Kubo S, Nemani VM, Chalkley RJ et al (2005) A combinatorial code for the interaction of alpha-synuclein with membranes. J Biol Chem 280:31664–31672

    Article  PubMed  CAS  Google Scholar 

  4. Davidson WS, Jonas A, Clayton DF et al (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443–9449

    Article  PubMed  CAS  Google Scholar 

  5. Ramakrishnan M, Jensen PH, Marsh D (2003) Alpha-synuclein association with phosphatidylglycerol probed by lipid spin labels. Biochemistry 42:12919–12926

    Article  PubMed  CAS  Google Scholar 

  6. Martinez Z, Zhu M, Han S et al (2007) GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry 46:1868–1877

    Article  PubMed  CAS  Google Scholar 

  7. Di Pasquale E, Fantini J, Chahinian H et al (2010) Altered ion channel formation by the Parkinson’s-disease-linked E46K mutant of alpha-synuclein is corrected by GM3 but not by GM1 gangliosides. J Mol Biol 397:202–218

    Article  PubMed  Google Scholar 

  8. Fantini J, Yahi N (2011) Molecular basis for the glycosphingolipid-binding specificity of α-synuclein: key role of tyrosine 39 in membrane insertion. J Mol Biol 408:654–669

    Article  PubMed  CAS  Google Scholar 

  9. Fantini J, Yahi N (2010) Molecular insights into amyloid regulation by membrane cholesterol and sphingolipids: common mechanisms in neurodegenerative diseases. Expert Rev Mol Med 12:e27

    Article  PubMed  Google Scholar 

  10. Butterfield SM, Lashuel HA (2010) Amyloidogenic protein-membrane interactions: mechanistic insight from model systems. Angew Chem Int Ed Engl 49:5628–5654

    Article  PubMed  CAS  Google Scholar 

  11. Aisenbrey C, Borowik T, Byström R et al (2008) How is protein aggregation in amyloidogenic diseases modulated by biological membranes? Eur Biophys J 37:247–255

    Article  PubMed  CAS  Google Scholar 

  12. Fantini J (2003) How sphingolipids bind and shape proteins: molecular basis of lipid-protein interactions in lipid shells, rafts and related biomembrane domains. Cell Mol Life Sci 60:1027–1032

    PubMed  CAS  Google Scholar 

  13. Sarnataro D, Campana V, Paladino S et al (2004) PrP(C) association with lipid rafts in the early secretory pathway stabilizes its cellular conformation. Mol Cell Biol 15:4031–4042

    Article  CAS  Google Scholar 

  14. Yanagisawa K, Odaka A, Suzuki N et al (1995) GM1 ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer’s disease. Nat Med 1:1062–1066

    Article  PubMed  CAS  Google Scholar 

  15. Choo-Smith LP, Garzon-Rodriguez GCC et al (1997) Acceleration of amyloid fibril formation by specific binding of Abeta-(1-40) peptide to ganglioside-containing membrane vesicles. J Biol Chem 272:22987–22990

    Article  PubMed  CAS  Google Scholar 

  16. Okada T, Wakabayashi M, Ikeda K (2007) Formation of toxic fibrils of Alzheimer’s amyloid beta-protein-(1-40) by monosialoganglioside GM1, a neuronal membrane component. J Mol Biol 371:481–489

    Article  PubMed  CAS  Google Scholar 

  17. Rochet JC, Lansbury PT Jr (2000) Amyloid fibrillo-genesis: themes and variations. Curr Opin Struct Biol 10:60–68

    Article  PubMed  CAS  Google Scholar 

  18. Quist A, Doudevski I, Lin H et al (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci USA 102:10427–10432

    Article  PubMed  CAS  Google Scholar 

  19. Arispe N, Rojas E, Pollard HB (1993) Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci USA 90:567–571

    Article  PubMed  CAS  Google Scholar 

  20. Zakharov SD, Hulleman JD, Dutseva EA et al (2007) Helical alpha-synuclein forms highly conductive ion channels. Biochemistry 46:14369–14379

    Article  PubMed  CAS  Google Scholar 

  21. Arispe N, Pollard HB, Rojas E (1994) beta-Amyloid Ca(2+)-channel hypothesis for neuronal death in Alzheimer disease. Mol Cell Biochem 140:119–125

    Article  PubMed  CAS  Google Scholar 

  22. Stroud RM, Reiling K, Wiener M (1998) Ion-channel-forming colicins. Curr Opin Struct Biol 8:525–533

    Article  PubMed  CAS  Google Scholar 

  23. Fantini J, Carlus D, Yahi N (2011) The fusogenic tilted peptide (67-78) of α-synuclein is a cholesterol binding domain. Biochim Biophys Acta 1808:2343–2351

    Article  PubMed  CAS  Google Scholar 

  24. Waheed AA, Freed EO (2010) The role of lipids in retrovirus replication. Viruses 2:1146–1180

    Article  PubMed  CAS  Google Scholar 

  25. Snook CF, Jones JA, Hannun YA (2006) Sphingolipid-binding proteins. Biochim Biophys Acta 1761:927–946

    Article  PubMed  CAS  Google Scholar 

  26. Taïeb N, Yahi N, Fantini J (2004) Rafts and related glycosphingolipid-enriched microdomains in the intestinal epithelium: bacterial targets linked to nutrient absorption. Adv Drug Deliv Rev 56:779–794

    Article  PubMed  Google Scholar 

  27. Yahi N, Aulas A, Fantini J (2010) How cholesterol constrains glycolipid conformation for optimal recognition of Alzheimer’s beta amyloid peptide (Abeta1-40). PLoS One 5:e9079

    Article  PubMed  Google Scholar 

  28. Mahfoud R, Garmy N, Maresca M et al (2002) Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins. J Biol Chem 277:11292–11296

    Article  PubMed  CAS  Google Scholar 

  29. Fantini J, Garmy N, Yahi N (2006) Prediction of glycolipid-binding domains from the amino acid sequence of lipid raft-associated proteins: application to HpaA, a protein involved in the adhesion of Helico-bacter pylori to gastrointestinal cells. Biochemistry 45:10957–10962

    Article  PubMed  CAS  Google Scholar 

  30. Levy M, Garmy N, Gazit E et al (2006) The minimal amyloid-forming fragment of the islet amyloid polypeptide is a glycolipid-binding domain. FEBS J 273:5724–5735

    Article  PubMed  CAS  Google Scholar 

  31. Fantini J (2007) Interaction of proteins with lipid rafts through glycolipid-binding domains: biochemical background and potential therapeutic applications. Curr Med Chem 14:2911–2917

    Article  PubMed  CAS  Google Scholar 

  32. Chakrabandhu K, Huault S, Garmy N et al (2008) The extracellular glycosphingolipid-binding motif of Fas defines its internalization route, mode and outcome of signals upon activation by ligand. Cell Death Differ 15:1824–1837

    Article  PubMed  CAS  Google Scholar 

  33. Taïeb N, Maresca M, Guo XJ et al (2009) The first extracellular domain of the tumour stem cell marker CD133 contains an antigenic ganglioside-binding motif. Cancer Lett 278:164–173

    Article  PubMed  Google Scholar 

  34. Nishio M, Umezawa Y, Hirota M et al (1995) The CH/pi interaction: significance in molecular recognition. Tetrahedron 51:8665–8701

    Article  CAS  Google Scholar 

  35. Ulmer TS, Bax A, Cole NB et al (2005) Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem 280:9595–9603

    Article  PubMed  CAS  Google Scholar 

  36. Desiraju GR, Steiner T (1999) The weak hydrogen bond in structural chemistry and biology. Oxford University Press, Oxford

    Google Scholar 

  37. Steiner T, Koellner G (2001) Hydrogen bonds with pi-acceptors in proteins: frequencies and role in stabilizing local 3D structures. J Mol Biol 305:535–557

    Article  PubMed  CAS  Google Scholar 

  38. Malone JF, Murray CM, Charlton MH et al (1997) X-H…[pi ] (phenyl) interactions. Theoretical and crystallographic observations. J Chem Soc Faraday Trans 93:3429–3436

    Article  CAS  Google Scholar 

  39. Thakur G, Micic M, Leblanc RM (2009) Surface chemistry of Alzheimer’s disease: a Langmuir monolayer approach. Colloids Surf B Biointerfaces 74:436–456

    Article  PubMed  CAS  Google Scholar 

  40. Williamson MP, Suzuki Y, Bourne NT et al (2006) Binding of amyloid beta-peptide to ganglioside micelles is dependent on histidine-13. Biochem J 397:483–490

    Article  PubMed  CAS  Google Scholar 

  41. Crowet JM, Lins L, Dupiereux I et al (2007) Tilted properties of the 67-78 fragment of alpha-synuclein are responsible for membrane destabilization and neurotoxicity. Proteins 68:936–947

    Article  PubMed  CAS  Google Scholar 

  42. Brasseur R, Pillot T, Lins L et al (1997) Peptides in membranes: tipping the balance of membrane stability. Trends Biochem Sci 22:167–171

    Article  PubMed  CAS  Google Scholar 

  43. Charloteaux B, Lorin A, Brasseur R et al (2009) The “Tilted Peptide Theory” links membrane insertion properties and fusogenicity of viral fusion peptides. Protein Pept Lett 16:718–725

    Article  PubMed  CAS  Google Scholar 

  44. Uversky VN, Li J, Souilac P et al (2002) Biophysical properties of the synucleins and their propensities to fibrillate. Inhibition of α-synuclein assembly by β- and γ-synucleins. J Biol Chem 277:11970–11978

    Article  PubMed  CAS  Google Scholar 

  45. Uversky VN, Dunker AK (2010) Understanding protein non-folding. Biochim Biophys Acta 1804:1231–1264

    Article  PubMed  CAS  Google Scholar 

  46. Yahi N, Sabatier JM, Baghdiguian S et al (1995) Synthetic multimeric peptides derived from the principal neutralization domain (V3 loop) of human immunodeficiency virus type 1 (HIV-1) gp120 bind to galactosylceramide and block HIV-1 infection in a human CD4-negative mucosal epithelial cell line. J Virol 69:320–325

    PubMed  CAS  Google Scholar 

  47. Yahi N, Fantini J, Baghdiguian S et al (1995) SPC3, a synthetic peptide derived from the V3 domain of human immunodeficiency virus type 1 (HIV-1) gp120, inhibits HIV-1 entry into CD4+ and CD4- cells by two distinct mechanisms. Proc Natl Acad Sci USA 92:4867–4871

    Article  PubMed  CAS  Google Scholar 

  48. Hammache D, Yahi N, Maresca M et al (1999) Human erythrocyte glycosphingolipids as alternative cofactors for human immunodeficiency virus type 1 (HIV-1) entry: evidence for CD4-induced interactions between HIV-1 gp120 and reconstituted membrane microdomains of glycosphingolipids (Gb3 and GM3). J Virol 73:5244–5528

    PubMed  CAS  Google Scholar 

  49. Fantini J, Garmy N, Mahfoud R et al (2002) Lipid rafts: structure, function and role in HIV, Alzheimer’s and prion diseases. Expert Rev Mol Med 4:1–22

    Article  PubMed  Google Scholar 

  50. El-Agnaf OM, Salem SA, Paleologou KE et al (2003) Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J 17:1945–1947

    PubMed  CAS  Google Scholar 

  51. Park JY, Kim KS, Lee SB et al (2009) On the mechanism of internalization of alpha-synuclein into microglia: roles of ganglioside GM1 and lipid raft. J Neurochem 110:400–411

    Article  PubMed  CAS  Google Scholar 

  52. Gagne JJ, Power MC (2010) Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology 74:995–1002

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. EA 4674, Interactions Moléculaires et Systèmes Membranaires, Faculté des Sciences Saint-Jérôme, Aix Marseille University, Avenue Escadrille Normandie-Niemen, 13013, Marseille, France

    Jacques Fantini & Nouara Yahi

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  1. Jacques Fantini
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  2. Nouara Yahi
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Correspondence to Nouara Yahi .

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Editors and Affiliations

  1. , Biological Sciences, Virginia Tech, Kraft Drive 1981, Blacksburg, 24061, Virginia, USA

    Daniel G.S. Capelluto

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Fantini, J., Yahi, N. (2013). The Driving Force of Alpha-Synuclein Insertion and Amyloid Channel Formation in the Plasma Membrane of Neural Cells: Key Role of Ganglioside- and Cholesterol-Binding Domains. In: Capelluto, D. (eds) Lipid-mediated Protein Signaling. Advances in Experimental Medicine and Biology, vol 991. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6331-9_2

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