Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity

International audienceSpontaneous aggregation of folded and soluble native proteins in vivo is still a poorlyunderstood process. A prototypic example is the D76N mutant of beta-2 microglobulin(β2m) that displays an aggressive aggregation propensity. Here we investigate the dynamicsof β2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations tounveil the effects of the D76N mutation. Taken together, our data highlight the presence ofminor disordered substates in crystalline β2m. The destabilization of the outer strandsof D76N β2m accounts for the increased aggregation propensity. Furthermore, thecomputational modeling reveals a network of interactions with residue D76 as a keystone:this model allows predicting the stability of several point mutants. Overall, our study showshow the study of intrinsic dynamics in crystallo can provide crucial answers on proteinstability and aggregation propensity. The comprehensive approach here presented may wellbe suited for the study of other folded amyloidogenic proteins