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Aggregation properties the controlling roles of Trp60 and Trp95 in beta(2)-microglobulin function, folding and amyloid aggregation properties (Articolo in rivista)

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Aggregation properties the controlling roles of Trp60 and Trp95 in beta(2)-microglobulin function, folding and amyloid aggregation properties (Articolo in rivista) (literal)

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Esposito, G; Ricagno, S; Corazza, A; Rennella, E; Gumral, 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)
Aggregation properties the controlling roles of Trp60 and Trp95 in beta(2)-microglobulin function, folding and amyloid aggregation properties
in Journal of Molecular Biology
(literal)

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Esposito, G; Ricagno, S; Corazza, A; Rennella, E; Gumral, 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 (literal)

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\"[Raimondi, Sara; Giorgetti, Sofia; Bolognesi, Benedetta; Merlini, Giampaolo; Stoppini, Monica; Bellotti, Vittorio] Univ Pavia, Dept Biochem, I-27100 Pavia, Italy; [Esposito, Gennaro; Corazza, Alessandra; Rennella, Enrico; Guemral, Devrim; Mimmi, Maria Chiara; Betto, Elena; Pucillo, Carlo E. M.; Fogolari, Federico; Viglino, Paolo] Univ Udine, Dept Biomed Sci & Technol, I-33100 Udine, Italy; [Ricagno, Stefano; Bolognesi, Martino] Univ Milan, CNR, Dept Biomol Sci & Biotechnol, INFM, I-20133 Milan, Italy; [Ricagno, Stefano; Bolognesi, Martino] Univ Milan, CIMAINA, I-20133 Milan, Italy; [Merlini, Giampaolo; Bellotti, Vittorio] Policlin San Matteo, Biotechnol Lab, Fdn IRCCS, I-27100 Pavia, Italy (literal)

Titolo

Aggregation properties the controlling roles of Trp60 and Trp95 in beta(2)-microglobulin function, folding and amyloid aggregation properties (literal)

Abstract

\"Amyloidosis associated to hemodialysis is caused by persistently high beta(2)-microglobulin (beta(2)m) serum levels. beta(2)m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no beta(2)m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to beta(2)m 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 beta(2)m 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 beta(2)m, inhibits beta(2)m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the beta(2)m core; the Trp95 -> Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar beta(2)m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in beta(2)m, 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 beta(2)m towards self-aggregation into amyloid fibrils. (c) 2008 Elsevier Ltd. All rights reserved.\" (literal)

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