title: Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin: roles of shear flow, hydrophobic surfaces, and α-crystallin.
abstract: Systemic amyloidosis is a fatal disease caused by misfolding of native globular proteins, which then aggregate extracellularly as insoluble fibrils, damaging the structure and function of affected organs. The formation of amyloid fibrils in vivo is poorly understood. We recently identified the first naturally occurring structural variant, D76N, of human β2-microglobulin (β2m), the ubiquitous light chain of class I major histocompatibility antigens, as the amyloid fibril protein in a family with a new phenotype of late onset fatal hereditary systemic amyloidosis. Here we show that, uniquely, D76N β2m readily forms amyloid fibrils in vitro under physiological extracellular conditions. The globular native fold transition to the fibrillar state is primed by exposure to a hydrophobic-hydrophilic interface under physiological intensity shear flow. Wild type β2m is recruited by the variant into amyloid fibrils in vitro but is absent from amyloid deposited in vivo. This may be because, as we show here, such recruitment is inhibited by chaperone activity. Our results suggest general mechanistic principles of in vivo amyloid fibrillogenesis by globular proteins, a previously obscure process. Elucidation of this crucial causative event in clinical amyloidosis should also help to explain the hitherto mysterious timing and location of amyloid deposition.
authors.affiliation: From 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: P Patrizia
authors.initials: PP
authors.lastname: Mangione
authors.forename: Gennaro
authors.initials: G
authors.lastname: Esposito
authors.forename: Annalisa
authors.initials: A
authors.lastname: Relini
authors.forename: Sara
authors.initials: S
authors.lastname: Raimondi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Corazza
authors.forename: Federico
authors.initials: F
authors.lastname: Fogolari
authors.forename: Amanda
authors.initials: A
authors.lastname: Penco
authors.forename: Yuji
authors.initials: Y
authors.lastname: Goto
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yagi
authors.forename: Ciro
authors.initials: C
authors.lastname: Cecconi
authors.forename: Mohsin M
authors.initials: MM
authors.lastname: Naqvi
authors.forename: Julian D
authors.initials: JD
authors.lastname: Gillmore
authors.forename: Philip N
authors.initials: PN
authors.lastname: Hawkins
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
authors.forename: Ranieri
authors.initials: R
authors.lastname: Rolandi
authors.forename: Graham W
authors.initials: GW
authors.lastname: Taylor
authors.forename: Mark B
authors.initials: MB
authors.lastname: Pepys
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
mesh_terms: D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D028226:Amyloidosis, Familial / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D038201:alpha-Crystallins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D038201:alpha-Crystallins; D001613:beta 2-Microglobulin
keywords: Amyloid; Chaperones; D76N β2-Microglobulin; Protein Aggregation; Protein Misfolding; Protein Stability; Shear Stress; Systemic Amyloidosis