title: X-ray absorption spectroscopy reveals a substantial increase of sulfur oxidation in transthyretin (TTR) upon fibrillization.
abstract: Transthyretin (TTR) amyloid fibrils are the main component of the amyloid deposits occurring in Familial Amyloidotic Polyneuropathy patients. This is 1 of 20 human proteins leading to protein aggregation disorders such as Alzheimer's and Creutzfeldt-Jakob diseases. The structural details concerning the association of the protein molecules are essential for a better understanding of the disease and consequently the design of new strategies for diagnosis and therapeutics. Disulfide bonds are frequently considered essential for the stability of protein aggregates and since in the TTR monomers there is one cysteine residue, it is important to determine unambiguously the redox state of sulfur present in the fibrils. In this work we used x-ray spectroscopy to further characterize TTR amyloid fibrils. The sulfur K-edge absorption spectra for the wild type and some amyloidogenic TTR variants in the soluble and fibrillar forms were analyzed. Whereas in the soluble proteins the thiol group from cysteine (R-SH) and the thioether group from methionine (R-S-CH(3)) are the most abundant forms, in the TTR fibrils there is a significant oxidation of sulfur to the sulfonate form in the cysteine residue and a partial oxidation of sulfur to sulfoxide in the methionine residues. Further interpretation of the data reveals that there are no disulfide bridges in the fibrillar samples and suggest conformational changes in the TTR molecule, namely in strand A and/or in its vicinity, upon fibril formation.
authors.affiliation: ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Largo Prof. Abel Salazar n 2, 4099-003 Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Gales
authors.forename: Isabel
authors.initials: I
authors.lastname: Cardoso
authors.forename: Barbara
authors.initials: B
authors.lastname: Fayard
authors.forename: Alexandre
authors.initials: A
authors.lastname: Quintanilha
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Saraiva
authors.forename: Ana M
authors.initials: AM
authors.lastname: Damas
mesh_terms: D052160:Benzothiazoles; D004577:Electron Probe Microanalysis; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013455:Sulfur / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D052160:Benzothiazoles; D011228:Prealbumin; D013844:Thiazoles; C009462:thioflavin T; D013455:Sulfur