Metal binding sheds light on mechanisms of amyloid assembly

β-2 microglobulin (β2m) is the protein responsible for amyloid deposition in Dialysis-Related Amyloidosis (DRA). Aggregation can be induced by various solution conditions including exposure to divalent metal, incubation at acidic pH, and limited proteolysis. Using Cu²⁺ as a trigger, we have trapped, isolated, and crystallized a stable oligomer of β2m that is populated under amyloidogenic solution conditions (Calabrese et al. Nat Struct Mol Biol 2008; 15:965–71). This structure reveals that Cu²⁺-binding is associated with dramatic conformational rearrangements. This has allowed us to postulate a set of structural changes common to all β2m aggregation pathways. Cu²⁺ serves as a potential trigger in other aggregation systems such as Aβ, α-synuclein, and mammalian Prion (PrP). A comparison of Cu²⁺ binding to β2m and PrP reveals common features. Therefore, in addition to providing insight into DRA, induction of structure by Cu²⁺ binding appears to be a recurring structural motif for pathological changes in conformation.Key words: amyloid, protein folding, dialysis-related amyloidosis, copper, β-2 microglobulin, prion