title: Structural Impact of Tau Phosphorylation at Threonine 231.
abstract: Phosphorylation of the microtubule-associated protein Tau influences the assembly and stabilization of microtubules and is deregulated in several neurodegenerative diseases. The high flexibility of Tau, however, has prevented an atomic-level description of its phosphorylation-induced structural changes. Employing an extensive set of distance and orientational restraints together with a novel ensemble calculation approach, we determined conformational ensembles of Tau fragments in the non-phosphorylated state and, when phosphorylated at T231/S235 or T231/S235/S237/S238, four important sites of phosphorylation in Alzheimer disease. Comparison of the molecular ensembles showed that phosphorylation of the regulatory T231 does not perturb the backbone conformation of the proximal microtubule-binding (225)KVAVVR(230) motif. Instead, phosphorylated T231 selectively engages in a salt bridge with R230 that can compete with the formation of intermolecular salt bridges to tubulin. Our study provides an ensemble description which will be useful for the analysis of conformational transitions in Tau and other intrinsically disordered proteins.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwalbe
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany; Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Harindranath
authors.initials: H
authors.lastname: Kadavath
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.affiliation: Institut de Biologie Structurale Jean-Pierre Ebel, CEA-CNRS-UJF UMR 5075, 41 Rue Jules Horowitz, Grenoble 38027, France.
authors.forename: Valery
authors.initials: V
authors.lastname: Ozenne
authors.affiliation: Institut de Biologie Structurale Jean-Pierre Ebel, CEA-CNRS-UJF UMR 5075, 41 Rue Jules Horowitz, Grenoble 38027, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Blackledge
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 53175 Bonn, Germany; CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), 37077 Göttingen, Germany; Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), University Medical Center Göttingen, 37073 Göttingen, Germany. Electronic address: markus.zweckstetter@dzne.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013912:Threonine / Q000737:chemistry* / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: C054369:MAPT protein, human; D010455:Peptides; D011994:Recombinant Proteins; D016875:tau Proteins; D013912:Threonine; D001120:Arginine