title: Structural characterization of binding of Cu(II) to tau protein.
abstract: Transition metals have been frequently recognized as risk factors in neurodegenerative disorders, and brain lesions associated with Alzheimer's disease are rich in Fe(III), Zn(II), and Cu(II). By using different biophysical techniques (nuclear magnetic resonance, circular dichroism, light scattering, and microcalorimetry), we have structurally characterized the binding of Cu(II) to a 198 amino acid fragment of the protein Tau that can mimic both the aggregation behavior and microtubule binding properties of the full-length protein. We demonstrate that Tau can specifically bind one Cu(II) ion per monomer with a dissociation constant in the micromolar range, an affinity comparable to the binding of Cu(II) to other proteins involved in neurodegenerative diseases. NMR spectroscopy showed that two short stretches of residues, (287)VQSKCGS (293) and (310)YKPVDLSKVTSKCGS (324), are primarily involved in copper binding, in agreement with mutational analysis. According to circular dichroism and NMR spectroscopy, Tau remains largely disordered upon binding to Cu(II), although a limited amount of aggregation is induced.
authors.affiliation: Department for NMR-Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Soragni
authors.forename: Barbara
authors.initials: B
authors.lastname: Zambelli
authors.forename: Marco D
authors.initials: MD
authors.lastname: Mukrasch
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Sadasivam
authors.initials: S
authors.lastname: Jeganathan
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.forename: Stefano
authors.initials: S
authors.lastname: Ciurli
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
mesh_terms: D000595:Amino Acid Sequence; D002151:Calorimetry; D002850:Chromatography, Gel; D003300:Copper / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D003300:Copper