Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin roles of shear flow, hydrophobic surfaces, and α-crystallin

P. Patrizia Mangione, Gennaro Esposito, Annalisa Relini, Sara Raimondi, Riccardo Porcari, Sofia Giorgetti, Alessandra Corazza, Federico Fogolari, Amanda Penco, Yuji Goto, Young Ho Lee, Hisashi Yagi, Ciro Cecconi, Mohsin M. Naqvi, Julian D. Gillmore, Philip N. Hawkins, Fabrizio Chiti, Ranieri Rolandi, Graham W. Taylor, Mark B. PepysMonica Stoppini, Vittorio Bellotti

Research output: Contribution to journalArticle

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 β2mreadily 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.

Original languageEnglish (US)
Pages (from-to)30917-30930
Number of pages14
JournalJournal of Biological Chemistry
Volume288
Issue number43
DOIs
StatePublished - Oct 25 2013

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Crystallins
Shear flow
Amyloid
Amyloidosis
Familial Amyloidosis
Amyloidogenic Proteins
Histocompatibility Antigens Class I
Proteins
Phenotype
Light

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin roles of shear flow, hydrophobic surfaces, and α-crystallin. / Mangione, P. Patrizia; Esposito, Gennaro; Relini, Annalisa; Raimondi, Sara; Porcari, Riccardo; Giorgetti, Sofia; Corazza, Alessandra; Fogolari, Federico; Penco, Amanda; Goto, Yuji; Lee, Young Ho; Yagi, Hisashi; Cecconi, Ciro; Naqvi, Mohsin M.; Gillmore, Julian D.; Hawkins, Philip N.; Chiti, Fabrizio; Rolandi, Ranieri; Taylor, Graham W.; Pepys, Mark B.; Stoppini, Monica; Bellotti, Vittorio.

In: Journal of Biological Chemistry, Vol. 288, No. 43, 25.10.2013, p. 30917-30930.

Research output: Contribution to journalArticle

Mangione, PP, Esposito, G, Relini, A, Raimondi, S, Porcari, R, Giorgetti, S, Corazza, A, Fogolari, F, Penco, A, Goto, Y, Lee, YH, Yagi, H, Cecconi, C, Naqvi, MM, Gillmore, JD, Hawkins, PN, Chiti, F, Rolandi, R, Taylor, GW, Pepys, MB, Stoppini, M & Bellotti, V 2013, 'Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin roles of shear flow, hydrophobic surfaces, and α-crystallin', Journal of Biological Chemistry, vol. 288, no. 43, pp. 30917-30930. https://doi.org/10.1074/jbc.M113.498857
Mangione, P. Patrizia ; Esposito, Gennaro ; Relini, Annalisa ; Raimondi, Sara ; Porcari, Riccardo ; Giorgetti, Sofia ; Corazza, Alessandra ; Fogolari, Federico ; Penco, Amanda ; Goto, Yuji ; Lee, Young Ho ; Yagi, Hisashi ; Cecconi, Ciro ; Naqvi, Mohsin M. ; Gillmore, Julian D. ; Hawkins, Philip N. ; Chiti, Fabrizio ; Rolandi, Ranieri ; Taylor, Graham W. ; Pepys, Mark B. ; Stoppini, Monica ; Bellotti, Vittorio. / Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin roles of shear flow, hydrophobic surfaces, and α-crystallin. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 43. pp. 30917-30930.
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AU - Raimondi, Sara

AU - Porcari, Riccardo

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AU - Corazza, Alessandra

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AU - Penco, Amanda

AU - Goto, Yuji

AU - Lee, Young Ho

AU - Yagi, Hisashi

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AU - Hawkins, Philip N.

AU - Chiti, Fabrizio

AU - Rolandi, Ranieri

AU - Taylor, Graham W.

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AU - Stoppini, Monica

AU - Bellotti, Vittorio

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N2 - 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 β2mreadily 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.

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