title: Predictive atomic resolution descriptions of intrinsically disordered hTau40 and α-synuclein in solution from NMR and small angle scattering.
abstract: The development of molecular descriptions of intrinsically disordered proteins (IDPs) is essential for elucidating conformational transitions that characterize common neurodegenerative disorders. We use nuclear magnetic resonance, small angle scattering, and molecular ensemble approaches to characterize the IDPs Tau and α-synuclein. Ensemble descriptions of IDPs are highly underdetermined due to the inherently large number of degrees of conformational freedom compared with available experimental measurements. Using extensive cross-validation we show that five different types of independent experimental parameters are predicted more accurately by selected ensembles than by statistical coil descriptions. The improvement increases in regions whose local sampling deviates from statistical coil, validating the derived conformational description. Using these approaches we identify enhanced polyproline II sampling in aggregation-nucleation sites, supporting suggestions that this region of conformational space is important for aggregation.
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwalbe
authors.affiliation: University Grenoble Alpes, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France; CNRS, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France; CEA, DSV, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France.
authors.forename: Valéry
authors.initials: V
authors.lastname: Ozenne
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bibow
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Jaremko
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Jaremko
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Michal
authors.initials: M
authors.lastname: Gajda
authors.affiliation: University Grenoble Alpes, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France; CNRS, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France; CEA, DSV, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France.
authors.forename: Malene Ringkjøbing
authors.initials: MR
authors.lastname: Jensen
authors.affiliation: CEASAR Research Center, 53175 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: CEASAR Research Center, 53175 Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: Department of NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany; Center for the Molecular Physiology of the Brain, University Medical Center, 37073 Göttingen, Germany. Electronic address: mazw@nmr.mpibpc.mpg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.affiliation: University Grenoble Alpes, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France; CNRS, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France; CEA, DSV, Protein Dynamics and Flexibility, Institut de Biologie Structurale, 38000 Grenoble, France. Electronic address: martin.blackledge@ibs.fr.
authors.forename: Martin
authors.initials: M
authors.lastname: Blackledge
mesh_terms: D000465:Algorithms; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008565:Membrane Proteins / Q000737:chemistry*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D011392:Proline; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012542:Scattering, Radiation; D051844:alpha-Synuclein / Q000737:chemistry*; D016875:tau Proteins
chemical_list: D064267:Intrinsically Disordered Proteins; D008565:Membrane Proteins; D011392:Proline; D051844:alpha-Synuclein; C054369:MAPT protein, human; D016875:tau Proteins