Pathological self-aggregation of β(2)-microglobulin: a challenge for protein biophysics

Abstract

The pathological aggregation of b(2)-microglobulin (b2m) is examined starting from the relevance of some structural aspects of the protein. The systemic deposition of b2m fibrils has been ascribed to several factors, but no conclusive evidence emerged so far. The characterization of b2m aggregates by direct investigation through electron microscopy, atomic force microscopy, solid state NMR and other solid state techniques provides important structural and morphological information on the assembly, but no clues about the mechanism of the aggregation process. The most relevant mechanistic hypotheses are critically reviewed. In addition to the mechanisms exclusively based on structural features, also the recently reported prion-like conversion is analyzed and shown to hardly comply with some established conditions of the fibrillogenic process. An alternative mechanism is recalled that does not require rare events and involves only the full-length protein in proximity of collagen, i.e. the environment that physiologically supports deposition.