DE loop mutations affect beta2-microglobulin stability and amyloid aggregation.
Beta2-microglobulin (beta2m) is the light chain component of class I major histocompatibility complex (MHC-I). beta2m is an intrinsically amyloidogenic protein that can assemble into amyloid fibrils in vitro and in vivo. Several recent reports suggested that the polypeptide loop comprised between beta-strands D and E of beta2m 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 beta2m stability have been highlighted by showing that the beta2m 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 beta2m 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 can affect beta2m stability and amyloid aggregation properties.
Department of Biomolecular Sciences and Biotechnology, CNR-INFM and CIMAINA, University of Milano, Milano, Italy.
Stefano
S
Ricagno
Matteo
M
Colombo
Matteo
M
de Rosa
Enrico
E
Sangiovanni
Sofia
S
Giorgetti
Sara
S
Raimondi
Vittorio
V
Bellotti
Martino
M
Bolognesi
D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D017433:Protein Structure, Secondary; D014961:X-Ray Diffraction; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D000682:Amyloid; D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin