title: Remodeling of the conformational ensemble of the repeat domain of tau by an aggregation enhancer.
abstract: Misfolding of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and several other neurodegenerative disorders. Because of the dynamic nature of the Tau protein, little is known about the changes in Tau structure that occur during misfolding. Here we studied the structural consequences upon binding of the repeat domain of Tau, which plays a key role in pathogenic aggregation, to an aggregation enhancer. By combining NMR experiments with molecular simulations we show that binding of the aggregation enhancer polyglutamic acid remodels the conformational ensemble of Tau. Our study thus provides insight into an early event during misfolding of Tau.
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.
authors.forename: Elias
authors.initials: E
authors.lastname: Akoury
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.
authors.forename: Marco D
authors.initials: MD
authors.lastname: Mukrasch
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, 53175, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, 53175, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Tepper
authors.affiliation: Institut de Biologie Structurale (IBS), CEA, CNRS, University Grenoble Alpes, Grenoble, 38044, France.
authors.forename: Valery
authors.initials: V
authors.lastname: Ozenne
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, 53175, Germany.|CAESAR Research Center, Ludwig-Erhard-Allee 2, Bonn, 53175, Germany, and MPI for Metabolism Resesearch, Hamburg Outstation, c/o DESY, 22607 Hamburg, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: Institut de Biologie Structurale (IBS), CEA, CNRS, University Grenoble Alpes, Grenoble, 38044, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Blackledge
authors.affiliation: Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, 37077, Germany.|German Center for Neurodegenerative Diseases (DZNE), Göttingen, 37075, Germany.|Department of Neurology, University Medical Center Göttingen, Göttingen, 37073, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D002942:Circular Dichroism; D003545:Cysteine / Q000378:metabolism*; D000067493:Dynamic Light Scattering; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011099:Polyglutamic Acid / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D017510:Protein Folding; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; D011099:Polyglutamic Acid; D003545:Cysteine
keywords: Alzheimer disease; NMR spectroscopy; Tau; protein misfolding; structure