title: Spectroscopic approaches to the conformation of tau protein in solution and in paired helical filaments.
abstract: The abnormal aggregation of the microtubule-associated protein tau into paired helical filaments is one the hallmarks of Alzheimer's disease. This aggregation is based in the partial formation of beta-structure. In contrast, the soluble protein shows a mostly random coil structure, as judged by circular dichroism, Fourier transform infrared, X-ray scattering and biochemical assays. Here, we review the basis of the natively unstructured character of tau, as well as recent studies of residual structure and long-range interactions between different domains of the protein. Analysis of the primary structure reveals a very low content of hydrophobic amino acids and a high content of charged residues, both of which tend to counteract a well-folded globular state of proteins. In the case of tau, the low overall hydrophobicity is sufficient to explain the lack of folding. This is in contrast to other proteins which also carry an excess charge at physiological pH. By tryptophan scanning mutagenesis and fluorimetry we found that most of the sequence is solvent exposed. Analysis of the hydrodynamic radii confirms a mostly random coil structure of various tau isoforms and tau domains. The proteins can be further expanded by denaturation with GdHCl which indicates some global folding. This was substantiated by a FRET-based approach where the distances between different domains of tau were determined. The combined data show that tau is mostly disordered and flexible but tends to assume a hairpin-like overall fold which may be important in the transition to a pathological aggregate.
authors.affiliation: Max Planck Unit for Structural Molecular Biology, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: von Bergen
authors.forename: S
authors.initials: S
authors.lastname: Barghorn
authors.forename: S
authors.initials: S
authors.lastname: Jeganathan
authors.forename: E-M
authors.initials: EM
authors.lastname: Mandelkow
authors.forename: E
authors.initials: E
authors.lastname: Mandelkow
mesh_terms: D000818:Animals; D006801:Humans; D020033:Protein Isoforms; D017433:Protein Structure, Secondary; D013057:Spectrum Analysis; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins