Glimpses of the molecular mechanisms of β₂-microglobulin fibril formation in vitro: Aggregation on a complex energy landscape

Abstract 

β₂-microglobulin (β₂m) is a 99-residue protein that aggregates to form amyloid fibrils in dialysis-related amyloidosis. The protein provides a powerful model for exploration of the structural molecular mechanisms of fibril formation from a full-length protein in vitro. Fibrils have been assembled from β₂m under both low pH conditions, where the precursor is disordered, and at neutral pH where the protein is initially natively folded. Here we discuss the roles of sequence and structure in amyloid formation, the current understanding of the structural mechanisms of the early stages of aggregation of β₂m at both low and neutral pH, and the common and distinct features of these assembly pathways.

Abbreviations: DRA, dialysis-related amyloidosis, NMR, nuclear magnetic resonance, SEC, size exclusion chromatography

Keywords: β₂-microglobulin, Amyloid fibrils, Mechanisms, Structure