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. Pepys & 2 others Monica 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

    Fingerprint

    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.
    @article{02f5f4c23bd340468dbc00eb16f83a7f,
    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 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.",
    author = "Mangione, {P. Patrizia} and Gennaro Esposito and Annalisa Relini and Sara Raimondi and Riccardo Porcari and Sofia Giorgetti and Alessandra Corazza and Federico Fogolari and Amanda Penco and Yuji Goto and Lee, {Young Ho} and Hisashi Yagi and Ciro Cecconi and Naqvi, {Mohsin M.} and Gillmore, {Julian D.} and Hawkins, {Philip N.} and Fabrizio Chiti and Ranieri Rolandi and Taylor, {Graham W.} and Pepys, {Mark B.} and Monica Stoppini and Vittorio Bellotti",
    year = "2013",
    month = "10",
    day = "25",
    doi = "10.1074/jbc.M113.498857",
    language = "English (US)",
    volume = "288",
    pages = "30917--30930",
    journal = "Journal of Biological Chemistry",
    issn = "0021-9258",
    publisher = "American Society for Biochemistry and Molecular Biology Inc.",
    number = "43",

    }

    TY - JOUR

    T1 - Structure, folding dynamics, and amyloidogenesis of D76N β2-microglobulin roles of shear flow, hydrophobic surfaces, and α-crystallin

    AU - Mangione, P. Patrizia

    AU - Esposito, Gennaro

    AU - Relini, Annalisa

    AU - Raimondi, Sara

    AU - Porcari, Riccardo

    AU - Giorgetti, Sofia

    AU - Corazza, Alessandra

    AU - Fogolari, Federico

    AU - Penco, Amanda

    AU - Goto, Yuji

    AU - Lee, Young Ho

    AU - Yagi, Hisashi

    AU - Cecconi, Ciro

    AU - Naqvi, Mohsin M.

    AU - Gillmore, Julian D.

    AU - Hawkins, Philip N.

    AU - Chiti, Fabrizio

    AU - Rolandi, Ranieri

    AU - Taylor, Graham W.

    AU - Pepys, Mark B.

    AU - Stoppini, Monica

    AU - Bellotti, Vittorio

    PY - 2013/10/25

    Y1 - 2013/10/25

    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.

    AB - 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.

    UR - http://www.scopus.com/inward/record.url?scp=84886655678&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84886655678&partnerID=8YFLogxK

    U2 - 10.1074/jbc.M113.498857

    DO - 10.1074/jbc.M113.498857

    M3 - Article

    VL - 288

    SP - 30917

    EP - 30930

    JO - Journal of Biological Chemistry

    JF - Journal of Biological Chemistry

    SN - 0021-9258

    IS - 43

    ER -