title: Co-fibrillogenesis of Wild-type and D76N β2-Microglobulin: THE CRUCIAL ROLE OF FIBRILLAR SEEDS.
abstract: The amyloidogenic variant of β2-microglobulin, D76N, can readily convert into genuine fibrils under physiological conditions and primes in vitro the fibrillogenesis of the wild-type β2-microglobulin. By Fourier transformed infrared spectroscopy, we have demonstrated that the amyloid transformation of wild-type β2-microglobulin can be induced by the variant only after its complete fibrillar conversion. Our current findings are consistent with preliminary data in which we have shown a seeding effect of fibrils formed from D76N or the natural truncated form of β2-microglobulin lacking the first six N-terminal residues. Interestingly, the hybrid wild-type/variant fibrillar material acquired a thermodynamic stability similar to that of homogenous D76N β2-microglobulin fibrils and significantly higher than the wild-type homogeneous fibrils prepared at neutral pH in the presence of 20% trifluoroethanol. These results suggest that the surface of D76N β2-microglobulin fibrils can favor the transition of the wild-type protein into an amyloid conformation leading to a rapid integration into fibrils. The chaperone crystallin, which is a mild modulator of the lag phase of the variant fibrillogenesis, potently inhibits fibril elongation of the wild-type even once it is absorbed on D76N β2-microglobulin fibrils.
authors.affiliation: From the Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy, the Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia (CNISM), UdR Milano-Bicocca, 20126 Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Natalello
authors.affiliation: the Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, United Kingdom, the Departments of Molecular Medicine, Institute of Biochemistry, and.
authors.forename: P Patrizia
authors.initials: PP
authors.lastname: Mangione
authors.affiliation: the Departments of Molecular Medicine, Institute of Biochemistry, and.
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.affiliation: the Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, United Kingdom.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.affiliation: the Departments of Molecular Medicine, Institute of Biochemistry, and.
authors.forename: Loredana
authors.initials: L
authors.lastname: Marchese
authors.affiliation: the Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy, and.
authors.forename: Irene
authors.initials: I
authors.lastname: Zorzoli
authors.affiliation: the Department of Physics, University of Genoa, 16146 Genoa, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Relini
authors.affiliation: From the Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy, the Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia (CNISM), UdR Milano-Bicocca, 20126 Milan, Italy.
authors.forename: Diletta
authors.initials: D
authors.lastname: Ami
authors.affiliation: the Departments of Molecular Medicine, Institute of Biochemistry, and.
authors.forename: Giulia
authors.initials: G
authors.lastname: Faravelli
authors.affiliation: the Departments of Molecular Medicine, Institute of Biochemistry, and.
authors.forename: Maurizia
authors.initials: M
authors.lastname: Valli
authors.affiliation: the Departments of Molecular Medicine, Institute of Biochemistry, and.
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
authors.affiliation: From the Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy, the Consorzio Nazionale Interuniversitario per le Scienze Fisiche della Materia (CNISM), UdR Milano-Bicocca, 20126 Milan, Italy.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Doglia
authors.affiliation: the Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, United Kingdom, the Departments of Molecular Medicine, Institute of Biochemistry, and.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.affiliation: the Departments of Molecular Medicine, Institute of Biochemistry, and sara.raimondi@unipv.it.
authors.forename: Sara
authors.initials: S
authors.lastname: Raimondi
mesh_terms: D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003459:Crystallins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D066263:Protein Aggregation, Pathological; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D003459:Crystallins; D018832:Molecular Chaperones; D001613:beta 2-Microglobulin
keywords: Fourier transform IR (FTIR); amyloid; fibril; protein aggregation; protein misfolding; β2-microglobulin