title: High-Affinity Binding of Monomeric but Not Oligomeric Amyloid-β to Ganglioside GM1 Containing Nanodiscs.
abstract: The interaction of the amyloid-β protein (Aβ) with neuronal cell membranes plays a crucial role in Alzheimer's disease. Aβ undergoes structural changes upon binding to ganglioside GM1 containing membranes leading to altered molecular characteristics of the protein. The physiological role of the Aβ interaction with the ganglioside GM1 is still unclear. In order to further elucidate the molecular requirements of Aβ membrane binding, we tested different nanodiscs varying in their lipid composition, regarding the charge of the headgroups as well as ganglioside GM1 concentration. Nanodiscs are excellent model membrane systems for studying protein membrane interactions, and we show here their suitability to investigate the membrane interaction of Aβ. In particular, we set out to investigate whether the binding activity of GM1 to Aβ is specific for the assembly state of Aβ and compared the binding affinities of monomeric with oligomeric Aβ. Using fluorescence titration experiments, we demonstrate high-affinity binding of Aβ(1-40) to GM1 containing nanodiscs, with dissociation constants, KD, in the range from 25 to 41 nM, in a GM1 concentration-dependent manner. Biolayer interferometry experiments confirmed the high-affinity binding of monomeric Aβ(1-40) (KDof 24 nM to 49 nM) as well as of Aβ(1-42) (KDof 30 nM) to GM1 containing nanodiscs, and no binding to phospholipid containing nanodiscs. Interestingly, and in contrast to monomeric Aβ, neither oligomeric Aβ(1-40) nor oligomeric Aβ(1-42) binds to GM1 nanodiscs. To the best of our knowledge, this is the first report of a loss of function for monomeric Aβ upon aggregation.
authors.affiliation: Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich , 52425, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Thomaier
authors.affiliation: Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich , 52425, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225, Düsseldorf, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.affiliation: Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich , 52425, Jülich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Dammers
authors.affiliation: Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich , 52425, Jülich, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Fabig
authors.affiliation: Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich , 52425, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225, Düsseldorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Neudecker
authors.affiliation: Institute of Complex Systems (ICS-6), Structural Biochemistry, Forschungszentrum Jülich , 52425, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005677:G(M1) Ganglioside / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D049329:Nanostructures / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization
chemical_list: D016229:Amyloid beta-Peptides; D008051:Lipid Bilayers; D010446:Peptide Fragments; D010743:Phospholipids; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005677:G(M1) Ganglioside