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

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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

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.
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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

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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.

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