title: Heparin induced dimerization of APP is primarily mediated by E1 and regulated by its acidic domain.
abstract: The amyloid precursor protein (APP) and its cellular processing are believed to be centrally involved in the etiology of Alzheimer's disease (AD). In addition, many physiological functions have been described for APP, including a role in cell-cell- and cell-ECM-adhesion as well as in axonal outgrowth. We show here the molecular determinants of the oligomerization/dimerization of APP, which is central for its cellular (mis)function. Using size exclusion chromatography (SEC), dynamic light scattering and SEC-coupled static light scattering we demonstrate that the dimerization of APP is energetically induced by a heparin mediated dimerization of the E1 domain, which results in a dimeric interaction of E2. We also show that the acidic domain (AcD) interferes with the dimerization of E1 and propose a model where both, cis- and trans-dimerization occur dependent on cellular localization and function.
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Protein Crystallography Group, Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hoefgen
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Protein Crystallography Group, Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Coburger
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Protein Crystallography Group, Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Roeser
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Protein Crystallography Group, Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schaub
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Protein Crystallography Group, Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Sven O
authors.initials: SO
authors.lastname: Dahms
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Protein Crystallography Group, Beutenbergstr. 11, 07745 Jena, Germany. Electronic address: than@fli-leibniz.de.
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Than
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics; D006493:Heparin / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013816:Thermodynamics
chemical_list: D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D006493:Heparin
keywords: Alzheimer’s disease; Amyloid precursor protein; Dimerization; Dynamic light scattering; Static light scattering