The Controlling Roles of Trp60 and Trp95 in β 2-Microglobulin Function, Folding and Amyloid Aggregation Properties

Amyloidosis associated to hemodialysis is caused by persistently high β 2-microglobulin (β 2m) serum levels. β 2m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no β 2m genetic variant is known in the human p...

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Published in:	Journal of molecular biology 2008, Vol.378 (4), p.887-897
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	amyloid fibrillogenesis NMR and X-ray structure determination role of tryptophans in β 2-microglobulin β 2-microglobulin
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Summary:	Amyloidosis associated to hemodialysis is caused by persistently high β 2-microglobulin (β 2m) serum levels. β 2m is an intrinsically amyloidogenic protein whose capacity to assemble into amyloid fibrils in vitro and in vivo is concentration dependent; no β 2m genetic variant is known in the human population. We investigated the roles of two evolutionary conserved Trp residues in relation to β 2m 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 β 2m 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 β 2m, inhibits β 2m amyloidogenic propensity and weakens the interaction with the class I major histocompatibility complex heavy chain. On the contrary, Trp95 is buried in the β 2m core; the Trp95 → Gly mutation destabilizes the protein, which is unfolded in solution, yielding nonfibrillar β 2m aggregates. Trp60 and Trp95 therefore play differential and complementary roles in β 2m, 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 β 2m towards self-aggregation into amyloid fibrils.
ISSN:	0022-2836 1089-8638