DE loop mutations affect β2-microglobulin stability and amyloid aggregation

beta 2-Microglobulin (beta 2m) is the light chain component of class I major histocompatibility complex (MHC-1). beta 2m is an intrinsically amyloidogenic protein that call assemble into amyloid fibrils ill vitro and ill vivo. Several recent reports Suggested that the polypeptide loop comprised between beta-strands D and E of beta 2m is important for protein stability and for the protein propensity to aggregate as amyloid fibrils. In particular. the roles of Trp60 for MHC-I assembly and beta 2m stability have been highlighted by showing that the beta 2m Trp60 -> Gly mutant is more stable and less prone to aggregation than the wild type protein. To further analyse such properties, the Trp60 -> Cys and Asp59 -> Pro beta 2m mutants have been expressed, purified, and their crystal structures determined. The stability to thermal denaturation and propensity to fibrillar aggregation have also been analysed. The experimental evidences gathered on the two mutants reinforce the hypothesis that conformational strain in the DE loop call affect beta 2m stability and amyloid aggregation properties. (C) 2008 Elsevier Inc. All rights reserved.