The Controlling Roles of Trp60 and Trp95 in β2-Microglobulin Function, Folding and Amyloid Aggregation Properties

Gennaro Esposito, Stefano Ricagno, Alessandra Corazza, Enrico Rennella, Devrim Gümral, Maria Chiara Mimmi, Elena Betto, Carlo E M Pucillo, Federico Fogolari, Paolo Viglino, Sara Raimondi, Sofia Giorgetti, Benedetta Bolognesi, Giampaolo Merlini, Monica Stoppini, Martino Bolognesi, Vittorio Bellotti

    Research output: Contribution to journalArticle

    Abstract

    Amyloidosis associated to hemodialysis is caused by persistently high β2-microglobulin (β2m) serum levels. β2m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no β2m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to β2m structure, function and folding/misfolding by means of a combined biophysical and functional approach. We show that Trp60 plays a functional role in promoting the association of β2m in class I major histocompatibility complex; it is exposed to the solvent at the apex of a protein loop in order to accomplish such function. The Trp60 → Gly mutation has a threefold effect: it stabilizes β2m, inhibits β2m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the β2m core; the Trp95 → Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar β2m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in β2m, being relevant for function (Trp60) and for maintenance of a properly folded structure (Trp95) while affecting in distinct ways the intrinsic propensity of wild-type β2m towards self-aggregation into amyloid fibrils.

    Original languageEnglish (US)
    Pages (from-to)885-895
    Number of pages11
    JournalJournal of Molecular Biology
    Volume378
    Issue number4
    DOIs
    StatePublished - May 9 2008

    Fingerprint

    Major Histocompatibility Complex
    Amyloid
    Amyloidogenic Proteins
    Mutation
    Amyloidosis
    Renal Dialysis
    Proteins
    Maintenance
    Serum
    Population
    In Vitro Techniques

    Keywords

    • β-microglobulin
    • amyloid
    • fibrillogenesis
    • NMR and X-ray structure determination
    • role of tryptophans in β-microglobulin

    ASJC Scopus subject areas

    • Virology

    Cite this

    Esposito, G., Ricagno, S., Corazza, A., Rennella, E., Gümral, D., Mimmi, M. C., ... Bellotti, V. (2008). The Controlling Roles of Trp60 and Trp95 in β2-Microglobulin Function, Folding and Amyloid Aggregation Properties. Journal of Molecular Biology, 378(4), 885-895. https://doi.org/10.1016/j.jmb.2008.03.002

    The Controlling Roles of Trp60 and Trp95 in β2-Microglobulin Function, Folding and Amyloid Aggregation Properties. / Esposito, Gennaro; Ricagno, Stefano; Corazza, Alessandra; Rennella, Enrico; Gümral, Devrim; Mimmi, Maria Chiara; Betto, Elena; Pucillo, Carlo E M; Fogolari, Federico; Viglino, Paolo; Raimondi, Sara; Giorgetti, Sofia; Bolognesi, Benedetta; Merlini, Giampaolo; Stoppini, Monica; Bolognesi, Martino; Bellotti, Vittorio.

    In: Journal of Molecular Biology, Vol. 378, No. 4, 09.05.2008, p. 885-895.

    Research output: Contribution to journalArticle

    Esposito, G, Ricagno, S, Corazza, A, Rennella, E, Gümral, D, Mimmi, MC, Betto, E, Pucillo, CEM, Fogolari, F, Viglino, P, Raimondi, S, Giorgetti, S, Bolognesi, B, Merlini, G, Stoppini, M, Bolognesi, M & Bellotti, V 2008, 'The Controlling Roles of Trp60 and Trp95 in β2-Microglobulin Function, Folding and Amyloid Aggregation Properties', Journal of Molecular Biology, vol. 378, no. 4, pp. 885-895. https://doi.org/10.1016/j.jmb.2008.03.002
    Esposito, Gennaro ; Ricagno, Stefano ; Corazza, Alessandra ; Rennella, Enrico ; Gümral, Devrim ; Mimmi, Maria Chiara ; Betto, Elena ; Pucillo, Carlo E M ; Fogolari, Federico ; Viglino, Paolo ; Raimondi, Sara ; Giorgetti, Sofia ; Bolognesi, Benedetta ; Merlini, Giampaolo ; Stoppini, Monica ; Bolognesi, Martino ; Bellotti, Vittorio. / The Controlling Roles of Trp60 and Trp95 in β2-Microglobulin Function, Folding and Amyloid Aggregation Properties. In: Journal of Molecular Biology. 2008 ; Vol. 378, No. 4. pp. 885-895.
    @article{50a745c2d2b44761b261e2ce3f29a35f,
    title = "The Controlling Roles of Trp60 and Trp95 in β2-Microglobulin Function, Folding and Amyloid Aggregation Properties",
    abstract = "Amyloidosis associated to hemodialysis is caused by persistently high β2-microglobulin (β2m) serum levels. β2m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no β2m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to β2m structure, function and folding/misfolding by means of a combined biophysical and functional approach. We show that Trp60 plays a functional role in promoting the association of β2m in class I major histocompatibility complex; it is exposed to the solvent at the apex of a protein loop in order to accomplish such function. The Trp60 → Gly mutation has a threefold effect: it stabilizes β2m, inhibits β2m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the β2m core; the Trp95 → Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar β2m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in β2m, being relevant for function (Trp60) and for maintenance of a properly folded structure (Trp95) while affecting in distinct ways the intrinsic propensity of wild-type β2m towards self-aggregation into amyloid fibrils.",
    keywords = "β-microglobulin, amyloid, fibrillogenesis, NMR and X-ray structure determination, role of tryptophans in β-microglobulin",
    author = "Gennaro Esposito and Stefano Ricagno and Alessandra Corazza and Enrico Rennella and Devrim G{\"u}mral and Mimmi, {Maria Chiara} and Elena Betto and Pucillo, {Carlo E M} and Federico Fogolari and Paolo Viglino and Sara Raimondi and Sofia Giorgetti and Benedetta Bolognesi and Giampaolo Merlini and Monica Stoppini and Martino Bolognesi and Vittorio Bellotti",
    year = "2008",
    month = "5",
    day = "9",
    doi = "10.1016/j.jmb.2008.03.002",
    language = "English (US)",
    volume = "378",
    pages = "885--895",
    journal = "Journal of Molecular Biology",
    issn = "0022-2836",
    publisher = "Academic Press Inc.",
    number = "4",

    }

    TY - JOUR

    T1 - The Controlling Roles of Trp60 and Trp95 in β2-Microglobulin Function, Folding and Amyloid Aggregation Properties

    AU - Esposito, Gennaro

    AU - Ricagno, Stefano

    AU - Corazza, Alessandra

    AU - Rennella, Enrico

    AU - Gümral, Devrim

    AU - Mimmi, Maria Chiara

    AU - Betto, Elena

    AU - Pucillo, Carlo E M

    AU - Fogolari, Federico

    AU - Viglino, Paolo

    AU - Raimondi, Sara

    AU - Giorgetti, Sofia

    AU - Bolognesi, Benedetta

    AU - Merlini, Giampaolo

    AU - Stoppini, Monica

    AU - Bolognesi, Martino

    AU - Bellotti, Vittorio

    PY - 2008/5/9

    Y1 - 2008/5/9

    N2 - Amyloidosis associated to hemodialysis is caused by persistently high β2-microglobulin (β2m) serum levels. β2m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no β2m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to β2m structure, function and folding/misfolding by means of a combined biophysical and functional approach. We show that Trp60 plays a functional role in promoting the association of β2m in class I major histocompatibility complex; it is exposed to the solvent at the apex of a protein loop in order to accomplish such function. The Trp60 → Gly mutation has a threefold effect: it stabilizes β2m, inhibits β2m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the β2m core; the Trp95 → Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar β2m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in β2m, being relevant for function (Trp60) and for maintenance of a properly folded structure (Trp95) while affecting in distinct ways the intrinsic propensity of wild-type β2m towards self-aggregation into amyloid fibrils.

    AB - Amyloidosis associated to hemodialysis is caused by persistently high β2-microglobulin (β2m) serum levels. β2m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no β2m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to β2m structure, function and folding/misfolding by means of a combined biophysical and functional approach. We show that Trp60 plays a functional role in promoting the association of β2m in class I major histocompatibility complex; it is exposed to the solvent at the apex of a protein loop in order to accomplish such function. The Trp60 → Gly mutation has a threefold effect: it stabilizes β2m, inhibits β2m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the β2m core; the Trp95 → Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar β2m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in β2m, being relevant for function (Trp60) and for maintenance of a properly folded structure (Trp95) while affecting in distinct ways the intrinsic propensity of wild-type β2m towards self-aggregation into amyloid fibrils.

    KW - β-microglobulin

    KW - amyloid

    KW - fibrillogenesis

    KW - NMR and X-ray structure determination

    KW - role of tryptophans in β-microglobulin

    UR - http://www.scopus.com/inward/record.url?scp=41949130213&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=41949130213&partnerID=8YFLogxK

    U2 - 10.1016/j.jmb.2008.03.002

    DO - 10.1016/j.jmb.2008.03.002

    M3 - Article

    VL - 378

    SP - 885

    EP - 895

    JO - Journal of Molecular Biology

    JF - Journal of Molecular Biology

    SN - 0022-2836

    IS - 4

    ER -