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Disordered Proteins: Biological Membranes as Two-Dimensional Aggregation Matrices

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Abstract

Aberrant folded proteins and peptides are hallmarks of amyloidogenic diseases. However, the molecular processes that cause these proteins to adopt non-native structures in vivo and become cytotoxic are still largely unknown, despite intense efforts to establish a general molecular description of their behavior. Clearly, the fate of these proteins is ultimately linked to their immediate biochemical environment in vivo. In this review, we focus on the role of biological membranes, reactive interfaces that not only affect the conformational stability of amyloidogenic proteins, but also their aggregation rates and, probably, their toxicity. We first provide an overview of recent work, starting with findings regarding the amphiphatic amyloid-β protein (Aβ), which give evidence that membranes can directly promote aggregation, and that the effectiveness in this process can be related to the presence of specific neuronal ganglioside lipids. In addition, we discuss the implications of recent research (medin as an detailed example) regarding putative roles of membranes in the misfolding behavior of soluble, non-amphiphatic proteins, which are attracting increasing interest. The potential role of membranes in exerting the toxic action of misfolded proteins will also be highlighted in a molecular context. In this review, we discuss novel NMR-based approaches for exploring membrane–protein interactions, and findings obtained using them, which we use to develop a molecular concept to describe membrane-mediated protein misfolding as a quasi-two-dimensional process rather than a three-dimensional event in a biochemical environment. The aim of the review is to provide researchers with a general understanding of the involvement of membranes in folding/misfolding processes in vivo, which might be quite universal and important for future research concerning amyloidogenic and misfolding proteins, and possible ways to prevent their toxic actions.

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References

  1. Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proceedings of the National Academy of Sciences of the United States of America, 82, 4245–4249.

    Article  PubMed  CAS  Google Scholar 

  2. Haass, C., & Selkoe, D. J. (1993). Cellular processing of beta-amyloid precursor protein and the genesis of amyloid beta-peptide. Cell, 75, 1039–1042.

    Article  PubMed  CAS  Google Scholar 

  3. Iversen, L. L., Mortishire-Smith, R. J., Pollack, S. J., & Shearman, M. S. (1995). The toxicity in vitro of beta-amyloid protein. Biochemical Journal, 311(Pt 1), 1–16.

    PubMed  CAS  Google Scholar 

  4. Rochet, J. C., & Lansbury, P. T., Jr. (2000). Amyloid fibrillogenesis: Themes and variations. Current Opinion in Structural Biology, 10, 60–68.

    Article  PubMed  CAS  Google Scholar 

  5. Bucciantini, M., Giannoni, E., Chiti, F., Baroni, F., Formigli, L., Zurdo, J., et al. (2002). Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature, 416, 507–511.

    Article  PubMed  CAS  Google Scholar 

  6. Glabe, C. G. (2006). Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiology of Aging, 27, 570–575.

    Article  PubMed  CAS  Google Scholar 

  7. Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., et al. (2003). Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science, 300, 486–489.

    Article  PubMed  CAS  Google Scholar 

  8. Petkova, A. T., Leapman, R. D., Guo, Z. H., Yau, W. M., Mattson, M. P., & Tycko, R. (2005). Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science, 307, 262–265.

    Article  PubMed  CAS  Google Scholar 

  9. Walsh, D. M., Hartley, D. M., Kusumoto, Y., Fezoui, Y., Condron, M. M., Lomakin, A., et al. (1999). Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. Journal of Biological Chemistry, 274, 25945–25952.

    Article  PubMed  CAS  Google Scholar 

  10. Klein, W. L., Stine, W. B., Jr., & Teplow, D. B. (2004). Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer’s disease. Neurobiology of Aging, 25, 569–580.

    Article  PubMed  CAS  Google Scholar 

  11. Haass, C., & Selkoe, D. J. (2007). Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid beta-peptide. Nature Reviews. Molecular Cell Biology, 8, 101–112.

    Article  PubMed  CAS  Google Scholar 

  12. Chimon, S., & Ishii, Y. (2005). Capturing intermediate structures of Alzheimer’s beta-amyloid, Abeta(1–40), by solid-state NMR spectroscopy. Journal of the American Chemical Society, 127, 13472–13473.

    Article  PubMed  CAS  Google Scholar 

  13. Zetterstrom, P., Stewart, H. G., Bergemalm, D., Jonsson, P. A., Graffmo, K. S., Andersen, P. M., et al. (2007). Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models. Proceedings of the National Academy of Sciences of the United States of America, 104, 14157–14162.

    Article  PubMed  CAS  Google Scholar 

  14. Velde, C. V., Miller, T. M., Cashman, N. R., & Cleveland, D. W. (2008). Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proceedings of the National Academy of Sciences of the United States of America, 105, 4022–4027.

    Article  CAS  Google Scholar 

  15. Walsh, D. M., Tseng, B. P., Rydel, R. E., Podlisny, M. B., & Selkoe, D. J. (2000). The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry, 39, 10831–10839.

    Article  PubMed  CAS  Google Scholar 

  16. Demeester, N., Baier, G., Enzinger, C., Goethals, M., Vandekerckhove, J., Rosseneu, M., et al. (2000). Apoptosis induced in neuronal cells by C-terminal amyloid beta-fragments is correlated with their aggregation properties in phospholipid membranes. Molecular Membrane Biology, 17, 219–228.

    Article  PubMed  CAS  Google Scholar 

  17. Kawahara, M., Kuroda, Y., Arispe, N., & Rojas, E. (2000). Alzheimer’s beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. Journal of Biological Chemistry, 275, 14077–14083.

    Article  PubMed  CAS  Google Scholar 

  18. Lin, H., Bhatia, R., & Lal, R. (2001). Amyloid beta protein forms ion channels: Implications for Alzheimer’s disease pathophysiology. FASEB Journal, 15, 2433–2444.

    Article  PubMed  CAS  Google Scholar 

  19. McLaurin, J., Yang, D., Yip, C. M., & Fraser, P. E. (2000). Review: Modulating factors in amyloid-beta fibril formation. Journal of Structural Biology, 130, 259–270.

    Article  PubMed  CAS  Google Scholar 

  20. Curtain, C. C., Ali, F. E., Smith, D. G., Bush, A. I., Masters, C. L., & Barnham, K. J. (2003). Metal ions, pH, and cholesterol regulate the interactions of Alzheimer’s disease amyloid-beta peptide with membrane lipid. Journal of Biological Chemistry, 278, 2977–2982.

    Article  PubMed  CAS  Google Scholar 

  21. Terzi, E., Holzemann, G., & Seelig, J. (1997). Interaction of Alzheimer beta-amyloid peptide(1–40) with lipid membranes. Biochemistry, 36, 14845–14852.

    Article  PubMed  CAS  Google Scholar 

  22. Simons, M., Keller, P., De Strooper, B., Beyreuther, K., Dotti, C. G., & Simons, K. (1998). Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America, 95, 6460–6464.

    Article  PubMed  CAS  Google Scholar 

  23. Scheuermann, S., Hambsch, B., Hesse, L., Stumm, J., Schmidt, C., Beher, D., et al. (2001). Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer’s disease. Journal of Biological Chemistry, 276, 33923–33929.

    Article  PubMed  CAS  Google Scholar 

  24. Engel, M. F. M., Khemtemourian, L., Kleijer, C. C., Meeldijk, H. J. D., Jacobs, J., Verkleij, A. J., et al. (2008). Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane. Proceedings of the National Academy of Sciences of the United States of America, 105, 6033–6038.

    Article  PubMed  CAS  Google Scholar 

  25. Shai, Y. (2002). Mode of action of membrane active antimicrobial peptides. Biopolymers, 66, 236–248.

    Article  PubMed  CAS  Google Scholar 

  26. Shai, Y. (1999). Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochimica et Biophysica Acta, 1462, 55–70.

    Article  PubMed  CAS  Google Scholar 

  27. Bonev, B. B., Chan, W. C., Bycroft, B. W., Roberts, G. C., & Watts, A. (2000). Interaction of the lantibiotic nisin with mixed lipid bilayers: A 31P and 2H NMR study. Biochemistry, 39, 11425–11433.

    Article  PubMed  CAS  Google Scholar 

  28. Wieprecht, T., Apostolov, O., Beyermann, M., & Seelig, J. (2000). Membrane binding and pore formation of the antibacterial peptide PGLa: Thermodynamic and mechanistic aspects. Biochemistry, 39, 442–452.

    Article  PubMed  CAS  Google Scholar 

  29. Seelig, J. (2004). Thermodynamics of lipid-peptide interactions. Biochimica et Biophysica Acta – Biomembranes, 1666, 40–50.

    CAS  Google Scholar 

  30. Giacomelli, C. E., & Norde, W. (2005). Conformational changes of the amyloid beta-peptide (1–40) adsorbed on solid surfaces. Macromolecular Bioscience, 5, 401–407.

    Article  PubMed  CAS  Google Scholar 

  31. Bokvist, M., Lindstrom, F., Watts, A., & Grobner, G. (2004). Two types of Alzheimer’s beta-amyloid (1–40) peptide membrane interactions: Aggregation preventing transmembrane anchoring versus accelerated surface fibril formation. Journal of Molecular Biology, 335, 1039–1049.

    Article  PubMed  CAS  Google Scholar 

  32. Bokvist, M., & Grobner, G. (2007). Misfolding of amyloidogenic proteins at membrane surfaces: The impact of macromolecular crowding. Journal of the American Chemical Society, 129, 14848–14849.

    Article  PubMed  CAS  Google Scholar 

  33. Maltseva, E., Kerth, A., Blume, A., Mohwald, H., & Brezesinski, G. (2005). Adsorption of amyloid beta (1–40) peptide at phospholipid monolayers. Chembiochem, 6, 1817–1824.

    Article  PubMed  CAS  Google Scholar 

  34. Zhao, H., Tuominen, E. K., & Kinnunen, P. K. (2004). Formation of amyloid fibers triggered by phosphatidylserine-containing membranes. Biochemistry, 43, 10302–10307.

    Article  PubMed  CAS  Google Scholar 

  35. Lindstrom, F., Bokvist, M., Sparrman, T., & Grobner, G. (2002). Association of amyloid-beta peptide with membrane surfaces monitored by solid state NMR. Physical Chemistry Chemical Physics, 4, 5524–5530.

    Article  CAS  Google Scholar 

  36. Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y., & Matsuzaki, K. (2002). Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: Importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry, 41, 7385–7390.

    Article  PubMed  CAS  Google Scholar 

  37. Waschuk, S. A., Elton, E. A., Darabie, A. A., Fraser, P. E., & McLaurin, J. A. (2001). Cellular membrane composition defines A beta-lipid interactions. Journal of Biological Chemistry, 276, 33561–33568.

    Article  PubMed  CAS  Google Scholar 

  38. Gibson Wood, W., Eckert, G. P., Igbavboa, U., & Muller, W. E. (2003). Amyloid beta-protein interactions with membranes and cholesterol: Causes or casualties of Alzheimer’s disease. Biochimica et Biophysica Acta, 1610, 281–290.

    Article  PubMed  CAS  Google Scholar 

  39. Devanathan, S., Salamon, Z., Lindblom, G., Grobner, G., & Tollin, G. (2006). Effects of sphingomyelin, cholesterol and zinc ions on the binding, insertion and aggregation of the amyloid Abeta(1–40) peptide in solid-supported lipid bilayers. FEBS Journal, 273, 1389–1402.

    Article  PubMed  CAS  Google Scholar 

  40. Aisenbrey, C., Borowik, T., Bystrom, R., Bokvist, M., Lindstrom, F., Misiak, H., et al. (2008). How is protein aggregation in amyloidogenic diseases modulated by biological membranes? European Biophysics Journal, 37, 247–255.

    Article  PubMed  CAS  Google Scholar 

  41. Mandal, P. K., & Pettegrew, J. W. (2004). Alzheimer’s disease: Soluble oligomeric A beta(1–40) peptide in membrane mimic environment from solution NMR and circular dichroism studies. Neurochemical Research, 29, 2267–2272.

    Article  PubMed  CAS  Google Scholar 

  42. Terzi, E., Holzemann, G., & Seelig, J. (1995). Self-association of beta-amyloid peptide(1–40) in solution and binding to lipid-membranes. Journal of Molecular Biology, 252, 633–642.

    Article  PubMed  CAS  Google Scholar 

  43. Simakova, O., & Arispe, N. J. (2006). Early and late cytotoxic effects of external application of the Alzheimer’s Abeta result from the initial formation and function of Abeta ion channels. Biochemistry, 45, 5907–5915.

    Article  PubMed  CAS  Google Scholar 

  44. Lal, R., Lin, H., & Quist, A. P. (2007). Amyloid beta ion channel: 3D structure and relevance to amyloid channel paradigm. Biochimica et Biophysica Acta, 1768, 1966–1975.

    Article  PubMed  CAS  Google Scholar 

  45. Olofsson, A., Borowik, T., Grobner, G., & Sauer-Eriksson, A. E. (2007). Negatively charged phospholipid membranes induce amyloid formation of medin via an alpha-helical intermediate. Journal of Molecular Biology, 374, 186–194.

    Article  PubMed  CAS  Google Scholar 

  46. Beyer, K. (2007). Mechanistic aspects of Parkinson’s disease: α-Synuclein and the membrane. Cell Biochemistry and Biophysics, 47, 285–299.

    Article  PubMed  CAS  Google Scholar 

  47. Lindstrom, F., Williamson, P. T. F., & Grobner, G. (2005). Molecular insight into the electrostatic membrane surface potential by N-14/P-31 MAS NMR spectroscopy: Nociceptin-lipid association. Journal of the American Chemical Society, 127, 6610–6616.

    Article  PubMed  CAS  Google Scholar 

  48. Minton, A. P. (1999). Adsorption of globular proteins on locally planar surfaces. II. Models for the effect of multiple adsorbate conformations on adsorption equilibria and kinetics. Biophysical Journal, 76, 176–187.

    PubMed  CAS  Google Scholar 

  49. Seelig, J. (1997). Titration calorimetry of lipid-peptide interactions. Biochimica et Biophysica Acta—Reviews on Biomembranes, 1331, 103–116.

    Article  CAS  Google Scholar 

  50. Murphy, R. M. (2007). Kinetics of amyloid formation and membrane interaction with amyloidogenic proteins. Biochimica et Biophysica Acta, 1768, 1923–1934.

    Article  PubMed  CAS  Google Scholar 

  51. Lau, T. L., Ambroggio, E. E., Tew, D. J., Cappai, R., Masters, C. L., Fidelio, G. D., et al. (2006). Amyloid-beta peptide disruption of lipid membranes and the effect of metal ions. Journal of Molecular Biology, 356, 759–770.

    Article  PubMed  CAS  Google Scholar 

  52. Sparr, E., Engel, M. F. M., Sakharov, D. V., Sprong, M., Jacobs, J., de Kruijff, B., et al. (2004). Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers. FEBS Letters, 577, 117–120.

    Article  PubMed  CAS  Google Scholar 

  53. Ravault, S., Soubias, O., Saurel, O., Thomas, A., Brasseur, R., & Milon, A. (2005). Fusogenic Alzheimer’s peptide fragment Abeta (29–42) in interaction with lipid bilayers: Secondary structure, dynamics, and specific interaction with phosphatidyl ethanolamine polar heads as revealed by solid-state NMR. Protein Science, 14, 1181–1189.

    Article  PubMed  CAS  Google Scholar 

  54. Munishkina, L. A., & Fink, A. L. (2007). Fluorescence as a method to reveal structures and membrane-interactions of amyloidogenic proteins. Biochimica et Biophysica Acta, 1768, 1862–1885.

    Article  PubMed  CAS  Google Scholar 

  55. Matsuzaki, K. (2007). Physicochemical interactions of amyloid beta-peptide with lipid bilayers. Biochimica et Biophysica Acta, 1768, 1935–1942.

    Article  PubMed  CAS  Google Scholar 

  56. Yip, C. M., & McLaurin, J. (2001). Amyloid-beta peptide assembly: A critical step in fibrillogenesis and membrane disruption. Biophysical Journal, 80, 1359–1371.

    PubMed  CAS  Google Scholar 

  57. Lopes, D. H., Meister, A., Gohlke, A., Hauser, A., Blume, A., & Winter, R. (2007). Mechanism of islet amyloid polypeptide fibrillation at lipid interfaces studied by infrared reflection absorption spectroscopy. Biophysical Journal, 93, 3132–3141.

    Article  PubMed  CAS  Google Scholar 

  58. Kremer, J. J., Sklansky, D. J., & Murphy, R. M. (2001). Profile of changes in lipid bilayer structure caused by beta-amyloid peptide. Biochemistry, 40, 8563–8571.

    Article  PubMed  CAS  Google Scholar 

  59. Barnham, K. J., Ciccotosto, G. D., Tickler, A. K., Ali, F. E., Smith, D. G., Williamson, N. A., et al. (2003). Neurotoxic, redox-competent Alzheimer’s beta-amyloid is released from lipid membrane by methionine oxidation. Journal of Biological Chemistry, 278, 42959–42965.

    Article  PubMed  CAS  Google Scholar 

  60. Esposito, C., Tedeschi, A., Scrima, M., D’Errico, G., Ottaviani, M. F., Rovero, P., et al. (2006). Exploring interaction of beta-amyloid segment (25–35) with membrane models through paramagnetic probes. Journal of Peptide Science, 12, 766–774.

    Article  PubMed  CAS  Google Scholar 

  61. Lau, T. L., Gehman, J. D., Wade, J. D., Perez, K., Masters, C. L., Barnham, K. J., et al. (2007). Membrane interactions and the effect of metal ions of the amyloidogenic fragment Abeta(25–35) in comparison to Abeta(1–42). Biochimica et Biophysica Acta, 1768, 2400–2408.

    Article  PubMed  CAS  Google Scholar 

  62. Veatch, S. L., Leung, S. S., Hancock, R. E., & Thewalt, J. L. (2007). Fluorescent probes alter miscibility phase boundaries in ternary vesicles. Journal of Physical Chemistry B, 111, 502–504.

    Article  CAS  Google Scholar 

  63. Seelig, J. (1978). 31P nuclear magnetic resonance and the head group structure of phospholipids in membranes. Biochimica et Biophysica Acta, 515, 105–140.

    PubMed  CAS  Google Scholar 

  64. Cullis, P. R., & de Kruijff, B. (1979). Lipid polymorphism and the functional roles of lipids in biological membranes. Biochimica et Biophysica Acta, 559, 399–420.

    PubMed  CAS  Google Scholar 

  65. Bechinger, B., & Seelig, J. (1991). Interaction of electric dipoles with phospholipid head groups—A H-2 and P-31 NMR-study of phloretin and phloretin analogs in phosphatidylcholine membranes. Biochemistry, 30, 3923–3929.

    Article  PubMed  CAS  Google Scholar 

  66. Macdonald, P. M., Leisen, J., & Marassi, F. M. (1991). Response of phosphatidylcholine in the gel and liquid-crystalline states to membrane surface charges. Biochemistry, 30, 3558–3566.

    Article  PubMed  CAS  Google Scholar 

  67. Roux, M., Neumann, J. M., Hodges, R. S., Devaux, P. F., & Bloom, M. (1989). Conformational changes of phospholipid headgroups induced by a cationic integral membrane peptide as seen by deuterium magnetic resonance. Biochemistry, 28, 2313–2321.

    Article  PubMed  CAS  Google Scholar 

  68. Sixl, F., & Watts, A. (1983). Headgroup interactions in mixed phospholipid bilayers. Proceedings of the National Academy of Sciences of the United States of America, 80, 1613–1615.

    Article  PubMed  CAS  Google Scholar 

  69. Pinheiro, T. J., & Watts, A. (1994). Resolution of individual lipids in mixed phospholipid membranes and specific lipid-cytochrome c interactions by magic-angle spinning solid-state phosphorus-31 NMR. Biochemistry, 33, 2459–2467.

    Article  PubMed  CAS  Google Scholar 

  70. Carbone, M. A., & Macdonald, P. M. (1996). Cardiotoxin II segregates phosphatidylglycerol from mixtures with phosphatidylcholine: (31)P and (2)H NMR spectroscopic evidence. Biochemistry, 35, 3368–3378.

    Article  PubMed  CAS  Google Scholar 

  71. Bonev, B. B., Breukink, E., Swiezewska, E., de Kruijff, B., & Watts, A. (2004). Targeting extracellular pyrophosphates underpins the high selectivity of nisin. FASEB Journal, 18, 1862–1869.

    Article  PubMed  CAS  Google Scholar 

  72. Seelig, J., Lehrmann, R., & Terzi, E. (1995). Domain formation induced by lipid ion and lipid peptide interactions. Molecular Membrane Biology, 12, 51–57.

    Article  PubMed  CAS  Google Scholar 

  73. Smith, D. P., Smith, D. G., Curtain, C. C., Boas, J. F., Pilbrow, J. R., Ciccotosto, G. D., et al. (2006). Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge. Journal of Biological Chemistry, 281, 15145–15154.

    Article  PubMed  CAS  Google Scholar 

  74. Lau, T. L., Gehman, J. D., Wade, J. D., Masters, C. L., Barnham, K. J., & Separovic, F. (2007). Cholesterol and clioquinol modulation of A beta(1–42) interaction with phospholipid bilayers and metals. Biochimica et Biophysica Acta, 1768, 3135–3144.

    Article  PubMed  CAS  Google Scholar 

  75. Caragounis, A., Du, T., Filiz, G., Laughton, K. M., Volitakis, I., Sharples, R. A., et al. (2007). Differential modulation of Alzheimer’s disease amyloid beta-peptide accumulation by diverse classes of metal ligands. Biochemical Journal, 407, 435–450.

    Article  PubMed  CAS  Google Scholar 

  76. Mandal, P. K., Pettegrew, J. W., Mckeag, D. W., & Mandal, R. (2006). Alzheimer’s disease: Halothane induces A beta peptide to oligomeric form-solution NMR studies. Neurochemical Research, 31, 883–890.

    Article  PubMed  CAS  Google Scholar 

  77. Chauhan, A., Ray, I., & Chauhan, V. P. (2000). Interaction of amyloid beta-protein with anionic phospholipids: Possible involvement of Lys28 and C-terminus aliphatic amino acids. Neurochemical Research, 25, 423–429.

    Article  PubMed  CAS  Google Scholar 

  78. Mobley, D. L., Cox, D. L., Singh, R. R., Maddox, M. W., & Longo, M. L. (2004). Modeling amyloid beta-peptide insertion into lipid bilayers. Biophysical Journal, 86, 3585–3597.

    Article  PubMed  CAS  Google Scholar 

  79. Rangachari, V., Reed, D. K., Moore, B. D., & Rosenberry, T. L. (2006). Secondary structure and interfacial aggregation of amyloid-beta(1–40) on sodium dodecyl sulfate micelles. Biochemistry, 45, 8639–8648.

    Article  PubMed  CAS  Google Scholar 

  80. Coles, M., Bicknell, W., Watson, A. A., Fairlie, D. P., & Craik, D. J. (1998). Solution structure of amyloid beta-peptide(1–40) in a water-micelle environment. Is the membrane-spanning domain where we think it is? Biochemistry, 37, 11064–11077.

    Article  PubMed  CAS  Google Scholar 

  81. Ji, S. R., Wu, Y., & Sui, S. F. (2002). Cholesterol is an important factor affecting the membrane insertion of beta-amyloid peptide (A beta 1–40), which may potentially inhibit the fibril formation. Journal of Biological Chemistry, 277, 6273–6279.

    Article  PubMed  CAS  Google Scholar 

  82. Kracun, I., Kalanj, S., Cosovic, C., & Talan-Hranilovic, J. (1990). Brain gangliosides in Alzheimer’s disease. Journal für Hirnforschung, 31, 789–793.

    PubMed  CAS  Google Scholar 

  83. Kracun, I., Kalanj, S., Talan-Hranilovic, J., & Cosovic, C. (1992). Cortical distribution of gangliosides in Alzheimer’s disease. Neurochemistry International, 20, 433–438.

    Article  PubMed  CAS  Google Scholar 

  84. Cordy, J. M., Hooper, N. M., & Turner, A. J. (2006). The involvement of lipid rafts in Alzheimer’s disease. Molecular Membrane Biology, 23, 111–122.

    Article  PubMed  CAS  Google Scholar 

  85. Williamson, R., Usardi, A., Hanger, D. P., & Anderton, B. H. (2008). Membrane-bound beta-amyloid oligomers are recruited into lipid rafts by a fyn-dependent mechanism. FASEB Journal, 22, 1552–1559.

    Article  PubMed  CAS  Google Scholar 

  86. Yanagisawa, K. (2007). Role of gangliosides in Alzheimer’s disease. Biochimica et Biophysica Acta, 1768, 1943–1951.

    Article  PubMed  CAS  Google Scholar 

  87. McLaurin, J., & Chakrabartty, A. (1996). Membrane disruption by Alzheimer beta-amyloid peptides mediated through specific binding to either phospholipids or gangliosides. Implications for neurotoxicity. Journal of Biological Chemistry, 271, 26482–26489.

    Article  PubMed  CAS  Google Scholar 

  88. McLaurin, J., Franklin, T., Fraser, P. E., & Chakrabartty, A. (1998). Structural transitions associated with the interaction of Alzheimer beta-amyloid peptides with gangliosides. Journal of Biological Chemistry, 273, 4506–4515.

    Article  PubMed  CAS  Google Scholar 

  89. Williamson, M. P., Suzuki, Y., Bourne, N. T., & Asakura, T. (2006). Binding of amyloid beta-peptide to ganglioside micelles is dependent on histidine-13. Biochemical Journal, 397, 483–490.

    Article  PubMed  CAS  Google Scholar 

  90. Choo-Smith, L. P., Garzon-Rodriguez, W., Glabe, C. G., & Surewicz, W. K. (1997). Acceleration of amyloid fibril formation by specific binding of Abeta-(1–40) peptide to ganglioside-containing membrane vesicles. Journal of Biological Chemistry, 272, 22987–22990.

    Article  PubMed  CAS  Google Scholar 

  91. Choo-Smith, L. P., & Surewicz, W. K. (1997). The interaction between Alzheimer amyloid beta(1–40) peptide and ganglioside GM1-containing membranes. FEBS Letters, 402, 95–98.

    Article  PubMed  CAS  Google Scholar 

  92. Ariga, T., Kobayashi, K., Hasegawa, A., Kiso, M., Ishida, H., & Miyatake, T. (2001). Characterization of high-affinity binding between gangliosides and amyloid beta-protein. Archives of Biochemistry and Biophysics, 388, 225–230.

    Article  PubMed  CAS  Google Scholar 

  93. Chi, E. Y., Frey, S. L., & Lee, K. Y. (2007). Ganglioside G(M1)-mediated amyloid-beta fibrillogenesis and membrane disruption. Biochemistry, 46, 1913–1924.

    Article  PubMed  CAS  Google Scholar 

  94. Matsuzaki, K., & Horikiri, C. (1999). Interactions of amyloid beta-peptide (1–40) with ganglioside-containing membranes. Biochemistry, 38, 4137–4142.

    Article  PubMed  CAS  Google Scholar 

  95. Kakio, A., Nishimoto, S. I., Yanagisawa, K., Kozutsumi, Y., & Matsuzaki, K. (2001). Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid. Journal of Biological Chemistry, 276, 24985–24990.

    Article  PubMed  CAS  Google Scholar 

  96. Okada, T., Wakabayashi, M., Ikeda, K., & Matsuzaki, K. (2007). Formation of toxic fibrils of Alzheimer’s amyloid beta-protein-(1–40) by monosialoganglioside GM1, a neuronal membrane component. Journal of Molecular Biology, 371, 481–489.

    Article  PubMed  CAS  Google Scholar 

  97. Wakabayashi, M., & Matsuzaki, K. (2007). Formation of amyloids by Abeta-(1–42) on NGF-differentiated PC12 cells: Roles of gangliosides and cholesterol. Journal of Molecular Biology, 371, 924–933.

    Article  PubMed  CAS  Google Scholar 

  98. Mandal, P. K., & Pettegrew, J. W. (2004). Alzheimer’s disease: NMR studies of asialo (GM1) and trisialo (GT1b) ganglioside interactions with Abeta(1–40) peptide in a membrane mimic environment. Neurochemical Research, 29, 447–453.

    Article  PubMed  CAS  Google Scholar 

  99. Fernandez, A., & Berry, R. S. (2003). Proteins with H-bond packing defects are highly interactive with lipid bilayers: Implications for amyloidogenesis. Proceedings of the National Academy of Sciences of the United States of America, 100, 2391–2396.

    Article  PubMed  CAS  Google Scholar 

  100. Fernandez, A., Kardos, J., Scott, L. R., Goto, Y., & Berry, R. S. (2003). Structural defects and the diagnosis of amyloidogenic propensity. Proceedings of the National Academy of Sciences of the United States of America, 100, 6446–6451.

    Article  PubMed  CAS  Google Scholar 

  101. Alakoskela, J. M., Jutila, A., Simonsen, A. C., Pirneskoski, J., Pyhajoki, S., Turunen, R., et al. (2006). Characteristics of fibers formed by cytochrome c and induced by anionic phospholipids. Biochemistry, 45, 13447–13453.

    Article  PubMed  CAS  Google Scholar 

  102. Gorbenko, G. P., & Kinnunen, P. K. (2006). The role of lipid-protein interactions in amyloid-type protein fibril formation. Chemistry and Physics of Lipids, 141, 72–82.

    Article  PubMed  CAS  Google Scholar 

  103. Mandal, P. K., Pettegrew, J. W., Masliah, E., Hamilton, R. L., & Mandal, R. (2006). Interaction between A beta peptide and alpha synuclein: Molecular mechanisms in overlapping pathology of Alzheimer’s and Parkinson’s in dementia with Lewy body disease. Neurochemical Research, 31, 1153–1162.

    Article  PubMed  CAS  Google Scholar 

  104. Brender, J. R., Durr, U. H., Heyl, D., Budarapu, M. B., & Ramamoorthy, A. (2007). Membrane fragmentation by an amyloidogenic fragment of human Islet Amyloid Polypeptide detected by solid-state NMR spectroscopy of membrane nanotubes. Biochimica et Biophysica Acta, 1768, 2026–2029.

    Article  PubMed  CAS  Google Scholar 

  105. Khemtemourian, L., Killian, J. A., Hoppener, J. W., & Engel, M. F. (2008). Recent insights in islet amyloid polypeptide-induced membrane disruption and its role in beta-cell death in type 2 diabetes mellitus. Experimental Diabetes Research, 2008, 421287.

    Article  PubMed  CAS  Google Scholar 

  106. Bruijn, L. I., Houseweart, M. K., Kato, S., Anderson, K. L., Anderson, S. D., Ohama, E., et al. (1998). Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science, 281, 1851–1854.

    Article  PubMed  CAS  Google Scholar 

  107. Lindberg, M. J., Bystrom, R., Boknas, N., Andersen, P. M., & Oliveberg, M. (2005). Systematically perturbed folding patterns of amyotrophic lateral sclerosis (ALS)-associated SOD1 mutants. Proceedings of the National Academy of Sciences of the United States of America, 102, 9754–9759.

    Article  PubMed  CAS  Google Scholar 

  108. Liu, J., Lillo, C., Jonsson, P. A., Velde, C. V., Ward, C. M., Miller, T. M., et al. (2004). Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron, 43, 5–17.

    Article  PubMed  CAS  Google Scholar 

  109. Haggqvist, B., Naslund, J., Sletten, K., Westermark, G. T., Mucchiano, G., Tjernberg, L. O., et al. (1999). Medin: An integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common human amyloid. Proceedings of the National Academy of Sciences of the United States of America, 96, 8669–8674.

    Article  PubMed  CAS  Google Scholar 

  110. Ceriani, R. L., Thompson, K., Peterson, J. A., & Abraham, S. (1977). Surface differentiation antigens of human mammary epithelial cells carried on the human milk fat globule. Proceedings of the National Academy of Sciences of the United States of America, 74, 582–586.

    Article  PubMed  CAS  Google Scholar 

  111. Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., & Nagata, S. (2002). Identification of a factor that links apoptotic cells to phagocytes. Nature, 417, 182–187.

    Article  PubMed  CAS  Google Scholar 

  112. Shi, J., Heegaard, C. W., Rasmussen, J. T., & Gilbert, G. E. (2004). Lactadherin binds selectively to membranes containing phosphatidyl-L-serine and increased curvature. Biochimica et Biophysica Acta, 1667, 82–90.

    Article  PubMed  CAS  Google Scholar 

  113. Shi, J., & Gilbert, G. E. (2003). Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites. Blood, 101, 2628–2636.

    Article  PubMed  CAS  Google Scholar 

  114. Taylor, M. R., Couto, J. R., Scallan, C. D., Ceriani, R. L., & Peterson, J. A. (1997). Lactadherin (formerly BA46), a membrane-associated glycoprotein expressed in human milk and breast carcinomas, promotes Arg-Gly-Asp (RGD)-dependent cell adhesion. DNA and Cell Biology, 16, 861–869.

    Article  PubMed  CAS  Google Scholar 

  115. Larsson, A., Peng, S., Wassberg, E., Gerwins, P., Thelin, S., & Westermark, P. (2006). Medin and medin-amyloid in thoracic aortic aneurysm and dissection. Amyloid—Journal of Protein Folding Disorders, 13, 40.

    Google Scholar 

  116. Larsson, A., Peng, S., Persson, H., Rosenbloom, J., Abrams, W. R., Wassberg, E., et al. (2006). Lactadherin binds to elastin—A starting point for medin amyloid formation? Amyloid—Journal of Protein Folding Disorders, 13, 78–85.

    CAS  Google Scholar 

  117. Larsson, A., Soderberg, L., Westermark, G. T., Sletten, K., Engstrom, U., Tjernberg, L. O., et al. (2007). Unwinding fibril formation of medin, the peptide of the most common form of human amyloid. Biochemical and Biophysical Research Communications, 361, 822–828.

    Article  PubMed  CAS  Google Scholar 

  118. Knight, J. D., Hebda, J. A., & Miranker, A. D. (2006). Conserved and cooperative assembly of membrane-bound alpha-helical states of islet amyloid polypeptide. Biochemistry, 45, 9496–9508.

    Article  PubMed  CAS  Google Scholar 

  119. Fezoui, Y., & Teplow, D. B. (2002). Kinetic studies of amyloid beta-protein fibril assembly. Differential effects of alpha-helix stabilization. Journal of Biological Chemistry, 277, 36948–36954.

    Article  PubMed  CAS  Google Scholar 

  120. Munishkina, L. A., Phelan, C., Uversky, V. N., & Fink, A. L. (2003). Conformational behavior and aggregation of alpha-synuclein in organic solvents: Modeling the effects of membranes. Biochemistry, 42, 2720–2730.

    Article  PubMed  CAS  Google Scholar 

  121. Kirkitadze, M. D., Condron, M. M., & Teplow, D. B. (2001). Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. Journal of Molecular Biology, 312, 1103–1119.

    Article  PubMed  CAS  Google Scholar 

  122. Barnham, K. J., Cappai, R., Beyreuther, K., Masters, C. L., & Hill, A. F. (2006). Delineating common molecular mechanisms in Alzheimer’s and prion diseases. Trends in Biochemical Sciences, 31, 465–472.

    Article  PubMed  CAS  Google Scholar 

  123. Ehrnhoefer, D. E., Bieschke, J., Boeddrich, A., Herbst, M., Masino, L., Lurz, R., et al. (2008). EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nature Structural & Molecular Biology, 15, 558–566.

    Article  CAS  Google Scholar 

  124. Chromy, B. A., Nowak, R. J., Lambert, M. P., Viola, K. L., Chang, L., Velasco, P. T., et al. (2003). Self-assembly of Abeta(1–42) into globular neurotoxins. Biochemistry, 42, 12749–12760.

    Article  PubMed  CAS  Google Scholar 

  125. Catalano, S. M., Dodson, E. C., Henze, D. A., Joyce, J. G., Krafft, G. A., & Kinney, G. G. (2006). The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer’s disease. Current Topics in Medicinal Chemistry, 6, 597–608.

    Article  PubMed  CAS  Google Scholar 

  126. Hepler, R. W., Grimm, K. M., Nahas, D. D., Breese, R., Dodson, E. C., Acton, P., et al. (2006). Solution state characterization of amyloid beta-derived diffusible ligands. Biochemistry, 45, 15157–15167.

    Article  PubMed  CAS  Google Scholar 

  127. Surolia, I., Sarkar, D. P., & Sinha, S. (2008). Form and dimensions of aggregates dictate cytotoxicities of Danish dementia peptides. Biochemical and Biophysical Research Communications, 372, 62–66.

    Article  PubMed  CAS  Google Scholar 

  128. de Planque, M. R., Raussens, V., Contera, S. A., Rijkers, D. T., Liskamp, R. M., Ruysschaert, J. M., et al. (2007). Beta-sheet structured beta-amyloid(1–40) perturbs phosphatidylcholine model membranes. Journal of Molecular Biology, 368, 982–997.

    Article  PubMed  CAS  Google Scholar 

  129. Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., et al. (2005). Regulation of NMDA receptor trafficking by amyloid-beta. Nature Neuroscience, 8, 1051–1058.

    Article  PubMed  CAS  Google Scholar 

  130. Langmuir, I. (1916). The constitution and fundamental properties of solids and liquids. Part I. Solids. Journal of the American Chemical Society, 38, 2221–2295.

    Article  CAS  Google Scholar 

  131. Beta, C., Moula, M. G., Mikhailov, A. S., Rotermund, H. H., & Ertl, G. (2004). Excitable CO oxidation on Pt(110) under nonuniform coupling. Physical Review Letters, 93, 188302.

    Article  PubMed  CAS  Google Scholar 

  132. White, S. H., & Wimley, W. C. (1999). Membrane protein folding and stability: Physical principles. Annual Review of Biophysics and Biomolecular Structure, 28, 319–365.

    Article  PubMed  CAS  Google Scholar 

  133. Minton, A. P. (2006). Macromolecular crowding. Current Biology, 16, R269–R271.

    Article  PubMed  CAS  Google Scholar 

  134. Talbot, J., Jin, X., & Wang, N. H. L. (1994). New equations for multicomponent adsorption-kinetics. Langmuir, 10, 1663–1666.

    Article  CAS  Google Scholar 

  135. Chatelier, R. C., & Minton, A. P. (1996). Adsorption of globular proteins on locally planar surfaces: Models for the effect of excluded surface area and aggregation of adsorbed protein on adsorption equilibria. Biophysical Journal, 71, 2367–2374.

    PubMed  CAS  Google Scholar 

  136. Aisenbrey, C., Bechinger, B., & Grobner, G. (2008). Macromolecular crowding at membrane interfaces: Adsorption and alignment of membrane peptides. Journal of Molecular Biology, 375, 376–385.

    Article  PubMed  CAS  Google Scholar 

  137. Sieber, J. J., Willig, K. I., Kutzner, C., Gerding-Reimers, C., Harke, B., Donnert, G., et al. (2007). Anatomy and dynamics of a supramolecular membrane protein cluster. Science, 317, 1072–1076.

    Article  PubMed  CAS  Google Scholar 

  138. Ellis, R. J. (2001). Macromolecular crowding: Obvious but underappreciated. Trends in Biochemical Sciences, 26, 597–604.

    Article  PubMed  CAS  Google Scholar 

  139. Heimburg, T., & Jackson, A. D. (2005). On soliton propagation in biomembranes and nerves. Proceedings of the National Academy of Sciences of the United States of America, 102, 9790–9795.

    Article  PubMed  CAS  Google Scholar 

  140. Raskin, D. M., & de Boer, P. A. J. (1999). MinDE-dependent pole-to-pole oscillation of division inhibitor MinC in Escherichia coli. Journal of Bacteriology, 181, 6419–6424.

    PubMed  CAS  Google Scholar 

  141. Durell, S. R., Guy, H. R., Arispe, N., Rojas, E., & Pollard, H. B. (1994). Theoretical models of the ion channel structure of amyloid beta-protein. Biophysical Journal, 67, 2137–2145.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Knut and Alice Wallenberg Foundation, Swedish Research Council (NT and Medicine), Umeå University Biotechnology Fund, Insamlingsstiftelse, Magn. Bergvalls Foundation, Carl Trygger Foundation, Alzheimerfonden, Socialstyrelsen, Hjärnfonden, Åke Wibergs Foundation, Göran Gustafssons Foundation, the Swedish Research Science Council, Ernst Schering Foundation, Centre for Biomedical Engineering at Wrocław University of Technology and the patients’ association FAMY/AMYL. We thank M. Oliveberg, S. Marklund, E. Sauer-Eriksson, G. Lindblom, L. Johansson, and E. Rosenbaum for all their support.

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  1. Fredrick Lindström

    Present address: Camurus AB, 223 70, Lund, Sweden

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  1. Department of Chemistry, Umeå University, 90187, Umeå, Sweden

    Roberth Byström, Christopher Aisenbrey, Marcus Bokvist, Fredrick Lindström, Marc-Antoine Sani & Gerhard Gröbner

  2. Institute of Biomedical Engineering, Wrocław University of Technology, 50 370, Wrocław, Poland

    Tomasz Borowik

  3. Umeå Centre for Molecular Pathogenesis, Umeå University, 901 87, Umeå, Sweden

    Anders Olofsson

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Appendix: Basics of Protein Membrane Adsorption

Appendix: Basics of Protein Membrane Adsorption

Surface physics and surface chemistry are well-established fields that have made major contributions to theoretical descriptions and practical applications of physico-chemical phenomena in physics and chemistry. Surfaces can provide templates for both physical and chemical processes (e.g., adsorption and catalytic reactions, respectively; [130, 131]) and can have highly specific properties due to their 2D nature. Traditionally, the main role of cells’ lipid membranes is separating intracellular compartments and the cell interior from its environment (thus maintaining cellular integrity). In this context, the membrane proteins play key roles in controlling the exchange of molecules and information. However, lipid membranes also provide large surface areas (relative to their enclosed volumes), and the lipid membrane surface area is close to maximal in some organelles (e.g., the endoplasmic reticulum, Golgi apparatus, and mitochondria). Hence, the specific properties of the membrane surfaces have the potential to play additional roles in cellular processes. It is, therefore, worthwhile to explore the role of lipid membranes as two-dimensional surface templates that facilitate cellular processes.

Adsorption Isotherms: Protein Surface Crowding

One possible approach to describe the adsorption of molecules to the membrane surface is to apply the equation for the intermolecular binding equilibrium in the form of [132]:

$$ K_{\text{assoc}} = \frac{{[{\text{PL}}]}}{{[{\text{P}}][{\text{L}}]}} $$
(1)

where [PL], [P], and [L] are the concentrations of lipid bound protein, free protein, and lipid, respectively. However, the description of intermolecular binding is poorly compatible with the process of molecule adsorption onto membrane. The equation fits only into a molecular picture, when the lipid concentration [L] is considered as the membrane surface area per volume. Also, in most cases intermolecular interactions between the adsorbed molecules are not negligible during surface adsorption.

Langmuir described the special properties of surfaces in his fundamental essay about “The constitution and fundamental properties of solids and liquids” [130] at the beginning of the last century. His description of adsorption of gases by solids, based on kinetic arguments (adsorption and desorption rates) are still the basis of surface physics.

$$ \Uptheta = \frac{\alpha P}{1 + \alpha P} $$
(2)

where Θ: surface coverage; α: constant; and P: gas pressure.

The equation reflects the necessity to consider intermolecular interactions on surfaces by introducing a surface coverage. The theory, however, idealizes intermolecular interactions by assuming an average occupancy of the surface per adsorbed molecule. But in a highly populated environment, the effective free space of a molecule is much lower than the average free space, due to the crowding effect [133].

For many processes, a more detailed description of the intermolecular interactions of adsorbed and free molecules is essential for any deeper mechanistic understanding. An analytic description of the membrane occupation, for example by a scaled particle theory [134], leads to a description of the effect of crowding on different adsorbed states [135, 136]. Notably the high surface occupancy favors the formation of multimeric states (Figs. 1 and 5). The analytical results were confirmed by experiments and computer simulations [137] for syntaxin 1, a protein involved in the initiation of membrane fusion [138].

However, the cell interior by itself with its high protein content of up to 200–300 g/l provides a crowded environment, which additionally affects the adsorption into the crowded membrane surface [32]. Here, the effect of crowding in the bulk volume on the adsorption of the amyloid Aβ has been demonstrated by the addition of ficoll, an inert macromolecule. In general, membrane surfaces can act as templates in numerous biological processes, ranging from electro-mechanical waves coupled to nerve pulse transmission to oscillating partition systems involved in cell division of Escherichia coli bacteria [131, 139, 140].

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Byström, R., Aisenbrey, C., Borowik, T. et al. Disordered Proteins: Biological Membranes as Two-Dimensional Aggregation Matrices. Cell Biochem Biophys 52, 175–189 (2008). https://doi.org/10.1007/s12013-008-9033-4

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