title: Fibrillation properties of human α₁-acid glycoprotein.
abstract: Human α(1)-acid glycoprotein (AGP) is a positive acute phase plasma protein containing two disulfide bridges. Structural studies have shown that under specific conditions AGP undergoes aggregation. In this study, we analysed the nature of AGP's aggregates formed under reducing and non-reducing conditions at pH 5.5 and at relatively low temperatures. Thioflavin T and Congo red spectroscopic analyses indicated the presence of cross-β structures in both unreduced and reduced AGP aggregates. In these samples amyloid-like fibrils were detected by transmission electron microscopy. The fibrils are branched and bent and present in very large amount in reduced AGP. Kinetics of AGP fibrillation proceeds without a lag phase and the rate constants of cross-β formation are linearly dependent on AGP concentration and result higher under reducing conditions. The data suggest a possible downhill mechanism of polymerization with a first-order monomer concentration dependence. Bioinformatics tools highlighted an extended region that sheathes one side of the molecule containing aggregation-prone regions. Reducing conditions make the extended region less constricted, allowing greater exposure of aggregation-prone regions, thus explaining the higher propensity of AGP to aggregate and fibrillate.
authors.affiliation: Dipartimento di Scienze della Vita e dell'Ambiente, Università Politecnica delle Marche, Via Ranieri, 60131 Ancona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Scirè
authors.forename: Maurizio
authors.initials: M
authors.lastname: Baldassarre
authors.forename: Roberta
authors.initials: R
authors.lastname: Galeazzi
authors.forename: Fabio
authors.initials: F
authors.lastname: Tanfani
mesh_terms: D000682:Amyloid / Q000737:chemistry; D052160:Benzothiazoles; D003224:Congo Red; D004220:Disulfides / Q000737:chemistry*; D005427:Flocculation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D056004:Molecular Dynamics Simulation; D009961:Orosomucoid / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013844:Thiazoles
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D004220:Disulfides; D009961:Orosomucoid; D013844:Thiazoles; C009462:thioflavin T; D003224:Congo Red